論文 - 小野寺　理

The Clinical Features, Risk Factors, and Surgical Treatment of Cervicogenic Headache in Patients With Cervical Spine Disorders Requiring Surgery 査読

Keiko Shimohata, Kazuhiro Hasegawa, Osamu Onodera, Masatoyo Nishizawa, Takayoshi Shimohata

HEADACHE   57 ( 7 )   1109 - 1117   2017年7月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Objective.-To clarify the clinical features and risk factors of cervicogenic headache (CEH; as diagnosed according to the International Classification of Headache Disorders-Third Edition beta) in patients with cervical spine disorders requiring surgery.
Background.-CEH is caused by cervical spine disorders. The pathogenic mechanism of CEH is hypothesized to involve a convergence of the upper cervical afferents from the C1, C2, and C3 spinal nerves and the trigeminal afferents in the trigeminocervical nucleus of the upper cervical cord. According to this hypothesis, functional convergence of the upper cervical and trigeminal sensory pathways allows the bidirectional (afferent and efferent) referral of pain to the occipital, frontal, temporal, and/or orbital regions. Previous prospective studies have reported an 86-88% prevalence of headache in patients with cervical myelopathy or radiculopathy requiring anterior cervical surgery; however, these studies did not diagnose headache according to the International Classification of Headache Disorders criteria. Therefore, a better understanding of the prevalence rate, clinical features, risk factors, and treatment responsiveness of CEH in patients with cervical spine disorders requiring surgery is necessary.
Methods.-We performed a single hospital-based prospective cross-sectional study and enrolled 70 consecutive patients with cervical spine disorders such as cervical spondylotic myelopathy, ossification of the posterior longitudinal ligament, cervical spondylotic radiculopathy, and cervical spondylotic myeloradiculopathy who had been scheduled to undergo anterior cervical fusion or dorsal cervical laminoplasty between June 2014 and December 2015. Headache was diagnosed preoperatively according to the International Classification of Headache Disorders-Third Edition beta. The Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire, Neck Disability Index, and a 0-100 mm visual analog scale (VAS) were used to evaluate clinical features, and scores were compared between baseline (ie, preoperatively) and 3, 6, and 12 months post-surgery.
Results.-The prevalence of CEH in our population was 15/70 (21.4%, 95% CI: 11.8% to 31.0%). The main clinical features were dull and tightening/pressing headache sensations in the occipital region. Headache severity was mild (VAS, 32611 mm) and only one patient reported use of an oral analgesic. Compared to patients without CEH, patients with CEH had higher frequencies of neck pain (86.7% vs. 50.9%; P=.017), cervical range of motion limitation (ROM) (66.7% vs. 38.2%; P=.049), and higher Neck Disability Index scores (14 vs. 3; P<.001). Among the different cervical spine disorders, the prevalence of CEH was highest in cervical spondylotic myeloradiculopathy patients (60%), being <= 20% for all other disorders. Surgical treatments including cervical laminoplasty to relieve abnormal pressure on the spinal cord via a posterior approach, were associated with initial improvements in headache VAS that slightly diminished by 12 months post-surgery (P<.001).
Conclusions.-We report a lower prevalence of CEH in patients with cervical spinal disorders requiring surgery than that reported previously. The main clinical features of CEH were mild, dull, and tightening/pressing headache sensations in the occipital region. Potential risk factors for CEH included neck pain, limited cervical ROM, high Neck Disability Index score, and a diagnosis of cervical spondylotic myeloradiculopathy. The further accumulation of patients in a multi-institutional study may be required in order to discuss the diagnostic criteria and pathophysiology of this condition.

DOI： 10.1111/head.13123

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Multiple system atrophy: clinicopathological characteristics in Japanese patients 査読

Tetsutaro Ozawa, Osamu Onodera

PROCEEDINGS OF THE JAPAN ACADEMY SERIES B-PHYSICAL AND BIOLOGICAL SCIENCES   93 ( 5 )   251 - 258   2017年5月

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記述言語：英語   出版者・発行元：JAPAN ACAD  

Multiple system atrophy (MSA) is an adult-onset neurodegenerative disorder that has both clinical and pathological variants. Clinical examples include MSA with predominant cerebellar ataxia (MSA-C) and MSA with predominant parkinsonism (MSA-P), whereas olivopontocerebellar atrophy and striatonigral degeneration represent pathological variants. We performed systematic reviews of studies that addressed the relative frequencies of clinical or pathological variants of MSA in various populations to determine the clinicopathological characteristics in Japanese MSA. The results revealed that the majority of Japanese patients have MSA-C, while the majority of patients in Europe and North America have MSA-P. A comparative study of MSA pathology showed that the olivopontocerebellar-predominant pathology was more frequent in Japanese MSA than in British MSA. Demonstrated differences in pathological subtype thus appear consistent with differences in the clinical subtype of MSA demonstrated between Japan and European populations. We concluded that olivopontocerebellar-predominant pathology and MSA-C may represent clinicopathological characteristics in Japanese MSA. Factors determining predominant involvement of olivopontocerebellar regions in MSA should therefore be explored.

DOI： 10.2183/pjab.93.016

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【Stroke-Like Diseases-鑑別時に注意を要する5病態】PRES Posterior Reversible Encephalopathy Syndrome 査読

岡本 浩一郎, 本橋 邦夫, 藤原 秀元, 石原 智彦, 二宮 格, 小野寺 理, 藤井 幸彦

BRAIN and NERVE: 神経研究の進歩   69 ( 2 )   129 - 141   2017年2月

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記述言語：日本語   出版者・発行元：(株)医学書院  

Posterior reversible encephalopathy syndromeは急激な血圧上昇・変動,腎不全,輸血,免疫抑制薬・抗癌薬使用,自己免疫疾患,子癇,敗血症などを背景に急性発症する神経疾患で,後頭葉・頭頂葉の血管性浮腫を特徴とする臨床的症候群である。脳出血や脳梗塞様所見を示す例もあり,脳卒中との鑑別が必要である。血管内皮障害が関与する病態を理解した早期診断・治療で改善が期待できる。(著者抄録)

DOI： 10.11477/mf.1416200653

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2017&ichushi_jid=J04871&link_issn=&doc_id=20170217120007&doc_link_id=10.11477%2Fmf.1416200653&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.1416200653&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

Familial amyotrophic lateral sclerosis with an I104F mutation in the SOD1 gene: Multisystem degeneration with neurofilamentous aggregates and SOD1 inclusions 査読

Haishan Jiang, Hiroshi Shimizu, Atsushi Shiga, Masami Tanaka, Osamu Onodera, Akiyoshi Kakita, Hitoshi Takahashi

NEUROPATHOLOGY   37 ( 1 )   69 - 77   2017年2月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

We previously reported familial amyotrophic lateral sclerosis (FALS) of 11years duration in a 57-year-old woman, who received artificial ventilation for 5years prior to death and exhibited widespread multisystem degeneration and neurofilamentous aggregates, so-called conglomerate inclusions (CIs). In the present study, we re-evaluated this autopsied patient (proband) with further immunohistochemical observation as well as mutational analysis of the superoxide dismutase 1 (SOD1) gene. A review of the clinical features of the proband's family revealed five affected members (including the proband) over two successive generations who showed marked variability in clinical presentation, such as the age at onset. The proband was found to harbor a heterozygous missense mutation in exon 4 (I104F) of the SOD1 gene. In the brain and spinal cord, SOD1-positive neuronal cytoplasmic inclusions (NCIs) were found to be more widely distributed than CIs, the latter being weakly positive for SOD1. No Lewy body-like hyaline inclusions were found. This is considered to be the first description of an autopsy case of FALS with an I104F SOD1 gene mutation, suggesting that combination of marked intra-familial clinical variability and multisystem degeneration with occurrence of CIs and SOD1-positive NCIs is a characteristic feature of FALS with this SOD1 gene mutation.

DOI： 10.1111/neup.12324

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Microglia preconditioned by oxygen-glucose deprivation promote functional recovery in ischemic rats 査読

Masato Kanazawa, Minami Miura, Masafumi Toriyabe, Misaki Koyama, Masahiro Hatakeyama, Masanori Ishikawa, Takashi Nakajima, Osamu Onodera, Tetsuya Takahashi, Masatoyo Nishizawa, Takayoshi Shimohata

SCIENTIFIC REPORTS   7   42582   2017年2月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

Cell-therapies that invoke pleiotropic mechanisms may facilitate functional recovery in stroke patients. We hypothesized that a cell therapy using microglia preconditioned by optimal oxygen-glucose deprivation (OGD) is a therapeutic strategy for ischemic stroke because optimal ischemia induces anti-inflammatory M2 microglia. We first delineated changes in angiogenesis and axonal outgrowth in the ischemic cortex using rats. We found that slight angiogenesis without axonal outgrowth were activated at the border area within the ischemic core from 7 to 14 days after ischemia. Next, we demonstrated that administration of primary microglia preconditioned by 18 hours of OGD at 7 days prompted functional recovery at 28 days after focal cerebral ischemia compared to control therapies by marked secretion of remodelling factors such as vascular endothelial growth factor, matrix metalloproteinase-9, and transforming growth factor-beta polarized to M2 microglia in vitro/vivo. In conclusion, intravascular administration of M2 microglia preconditioned by optimal OGD may be a novel therapeutic strategy against ischemic stroke.

DOI： 10.1038/srep42582

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Characteristic Brain MRI Features of Manifesting Heterozygotes With Cerebral Autosomal Recessive Arteriopathy With Subcortical Infarcts and Leukoencephalopathy

Masahiro Uemura, Hiroaki Nozaki, Yumi Sekine, Ikuko Mizuta, Tomoko Noda, Kazuhide Miyazaki, Muichi Kaito, Yoshinori Nishimoto, Yutaka Shimoe, Akiko Shirata, Kiyomi Yamane, Sohei Yanagawa, Mikio Hirayama, Masato Tamura, Toshiki Mizuno, Masatoyo Nishizawa, Osamu Onodera

STROKE   48   2017年2月

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記述言語：英語   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

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Clinical and genetic characterization of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia associated with CSF1R mutation 査読

T. Konno, K. Yoshida, T. Mizuno, T. Kawarai, M. Tada, H. Nozaki, S. I. Ikeda, M. Nishizawa, O. Onodera, Z. K. Wszolek, T. Ikeuchi

European Journal of Neurology   24 ( 1 )   37 - 45   2017年1月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Blackwell Publishing Ltd  

Background and purpose: The clinical characteristics of colony stimulating factor 1 receptor (CSF1R) related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) have been only partially elucidated. Methods: Clinical data from CSF1R mutation carriers who had been seen at our institutions or reported elsewhere were collected and analysed using a specific investigation sheet to standardize the data. Results: In all, 122 cases from 90 families with CSF1R mutations were identified. The mean age of onset was 43 years (range 18–78 years), the mean age at death was 53 years (range 23–84 years) and the mean disease duration was 6.8 years (range 1–29 years). Women had a significantly younger age of onset than men (40 vs. 47 years, P = 0.0006, 95% confidence interval 3.158–11.177). There was an age-dependent penetrance that was significantly different between the sexes (P = 0.0013). Motor dysfunctions were the most frequent initial symptom in women whose diseases began in their 20s. Thinning of the corpus callosum, abnormal signalling in pyramidal tracts, diffusion-restricted lesions and calcifications in the white matter were characteristic imaging findings of ALSP. The calcifications were more frequently reported in our case series than in the literature (54% vs. 3%). Seventy-nine per cent of the mutations were located in the distal part of the tyrosine kinase domain of CSF1R (102 cases). There were no apparent phenotype−genotype correlations. Conclusions: The characteristics of ALSP were clarified. The phenotype of ALSP caused by CSF1R mutations is affected by sex.

DOI： 10.1111/ene.13125

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Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) 査読

Masahiro Uemura, Hiroaki Nozaki, Osamu Onodera

Brain and Nerve   69 ( 1 )   25 - 33   2017年1月

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Igaku-Shoin Ltd  

Cerebral small vessel disease (CSVD) is frequently observed among the elderly and is known to cause dementia and gait disturbance associated with white matter lesions, lacunar infarcts, and cerebral hemorrhage. Molecular mechanistic studies promise to provide new insights into the pathogenesis of hereditary CSVD. Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is one of the hereditary CSVDs caused by a mutation in the hightemperature requirement serine peptidase A1 (HTRA1) gene. The loss of HTRA1 protease activity increases signaling via transforming growth factor (TGF)β, thereby resulting in CARASIL. Although the CARASIL has been characterized by juvenile onset alopecia and spondylosis deformans, these features are not always observed in individuals with an HTRA1 mutation. Moreover, some HTRA1 mutations cause CSVD in heterozygous states. Therefore, the clinical features of CSVD resulting from an HTRA1 mutation extend to patients with CSVD alone or to those with dominantly inherited CSVD.

DOI： 10.11477/mf.1416200631

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Clinical and genetic characterization of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia associated with CSF1R mutation 査読

T. Konno, K. Yoshida, T. Mizuno, T. Kawarai, M. Tada, H. Nozaki, S. -I. Ikeda, M. Nishizawa, O. Onodera, Z. K. Wszolek, T. Ikeuchi

EUROPEAN JOURNAL OF NEUROLOGY   24 ( 1 )   37 - 45   2017年1月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Background and purpose: The clinical characteristics of colony stimulating factor 1 receptor (CSF1R) related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) have been only partially elucidated.
Methods: Clinical data from CSF1R mutation carriers who had been seen at our institutions or reported elsewhere were collected and analysed using a specific investigation sheet to standardize the data.
Results: In all, 122 cases from 90 families with CSF1R mutations were identified. The mean age of onset was 43 years (range 18-78 years), the mean age at death was 53 years (range 23-84 years) and the mean disease duration was 6.8 years (range 1-29 years). Women had a significantly younger age of onset than men (40 vs. 47 years, P = 0.0006, 95% confidence interval 3.158-11.177). There was an age-dependent penetrance that was significantly different between the sexes (P = 0.0013). Motor dysfunctions were the most frequent initial symptom in women whose diseases began in their 20s. Thinning of the corpus callosum, abnormal signalling in pyramidal tracts, diffusion-restricted lesions and calcifications in the white matter were characteristic imaging findings of ALSP. The calcifications were more frequently reported in our case series than in the literature (54% vs. 3%). Seventy-nine per cent of the mutations were located in the distal part of the tyrosine kinase domain of CSF1R (102 cases). There were no apparent phenotype similar to genotype correlations.
Conclusions: The characteristics of ALSP were clarified. The phenotype of ALSP caused by CSF1R mutations is affected by sex.

DOI： 10.1111/ene.13125

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Diagnostic Value of Brain Calcifications in Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia 査読

T. Konno, D. F. Broderick, N. Mezaki, A. Isami, D. Kaneda, Y. Tashiro, T. Tokutake, B. M. Keegan, B. K. Woodruff, T. Miura, H. Nozaki, M. Nishizawa, O. Onodera, Z. K. Wszolek, T. Ikeuchi

AMERICAN JOURNAL OF NEURORADIOLOGY   38 ( 1 )   77 - 83   2017年1月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC NEURORADIOLOGY  

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia is a rare neurodegenerative disease resulting from mutations in the colony stimulating factor 1 receptor gene. Accurate diagnosis can be difficult because the associated clinical and MR imaging findings are nonspecific. We present 9 cases with intracranial calcifications distributed in 2 brain regions: the frontal white matter adjacent to the anterior horns of the lateral ventricles and the parietal subcortical white matter. Thin-section (1-mm) CT scans are particularly helpful in detection due to the small size of the calcifications. These calcifications had a symmetric "stepping stone appearance" in the frontal pericallosal regions, which was clearly visible on reconstructed sagittal CT images. Intrafamilial variability was seen in 2 of the families, and calcifications were seen at birth in a single individual. These characteristic calcification patterns may assist in making a correct diagnosis and may contribute to understanding of the pathogenesis of leukoencephalopathy.

DOI： 10.3174/ajnr.A4938

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A CARASIL Patient from Americas with Novel Mutation and Atypical Features: Case Presentation and Literature Review 査読

Muhammad Ibrahimi, Hiroaki Nozaki, Angelica Lee, Osamu Onodera, Raymond Reichwein, Matthew Wicklund, Mohammad El-Ghanem

CEREBROVASCULAR DISEASES   44 ( 3-4 )   135 - 140   2017年

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記述言語：英語   出版者・発行元：KARGER  

Objective: Reporting a novel mutation in the HTRA1 gene in a CARASIL patient from Americas. Methods: Clinical presentation and neuroimaging were consistent with CARASIL. HTRA1 DNA sequencing was performed using advanced ("next generation") sequencing technology. The results revealed a homozygous missense mutation as c.616G>A (p.Gly206Arg) in the HTRA1 gene. Results: A 24-year-old man with a history of chronic back pain presented with recurrent ischemic strokes. A diagnosis of CARASIL was made with the finding of a novel homozygous missense mutation c.616G>A in HTRA1 gene, resulting in change from Glycine to Arginine in the Serine Protease HTRA1. Brain imaging showed multiple lacunar infarcts with extensive abnormalities of the white matter that spared the external capsules. He also had unilateral decreased hearing with craniofacial asymmetry. None of the above features have been previously described in known CARASIL patients. Both parents of the proband were heterozygous for the same missense mutation. Conclusion: We discovered a novel missense mutation (c.616G>A) associated with a phenotype of CARASIL. This is the first genetically backed case of CARASIL in the new world. The patient's craniofacial abnormalities, including asymmetry of the head, may be related to impaired modulation of transforming growth factor-beta 1, the result of loss of proteolytic activity of HTRA1. External capsules remained unaffected, despite findings of advanced changes in the rest of the cerebral white matter. Literature is briefly reviewed. The patient's history, neurological exam, neuroimaging, and genetic testing are included. (C) 2017 S. Karger AG, Basel

DOI： 10.1159/000477358

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Dissociation between intact vibratory sensation and impaired joint position sensation may predict ataxia of spinal origin 査読

Masato Kanazawa, Keiichi Katsumi, Takayoshi Tokutake, Naoto Endo, Osamu Onodera, Masatoyo Nishizawa

Interdisciplinary Neurosurgery: Advanced Techniques and Case Management   6   68 - 70   2016年12月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier B.V.  

Vibratory and joint position sensations are usually impaired simultaneously and afferents for both sensations ascend the dorsal columns. There are a few evidences that the central pathways in the spinal cord for position and vibratory sensations are not identical. In this study, we examined the clinical features of patients with sensory impairments of vibratory and joint position sensations. According to 43 evaluated patients’ results, the dissociation between an intact vibratory sensation and impaired joint position sensation may be important for the diagnosis of spinal disorders. We also report three cases of patients with spinal ataxia caused by sensory impairments and who show the dissociation between an impaired joint position sensation and an intact vibratory sensation. The combination of intact vibration sensation and impaired joint position sensation may suggest a dorsal column lesion in the spinal cord.

DOI： 10.1016/j.inat.2016.09.003

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その他リンク： http://orcid.org/0000-0001-6337-8156

Performance of a real-time PCR-based approach and droplet digital PCR in detecting human parechovirus type 3 RNA 査読

Yuta Aizawa, Akihide Koyama, Tomohiko Ishihara, Osamu Onodera, Akihiko Saitoh

JOURNAL OF CLINICAL VIROLOGY   84   27 - 31   2016年11月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

Background: Human parechovirus type 3 (HPeV3) is an emerging virus that causes sepsis and meningoencephalitis in neonates and young infants. Correct diagnosis of HPeV3 infection is critical in determining appropriate management and predicting patients' clinical course. Real-time reverse transcription PCR (RT-PCR) analysis of serum and/or cerebrospinal fluid (CSF) has been used to diagnose HPeV3 infection; however, the assay detection limits have not been fully evaluated.
Objectives: We tested the hypothesis that droplet digital RT-PCR (RT-ddPCR) a novel technique that precisely quantitates low-copy target genes by diluting and partitioning samples into compartments increases the detection rate of HPeV3 RNA as compared with real-time RT-PCR.
Study design: Using samples with predetermined HPeV3 copy numbers, we evaluated one-step and two-step RT-ddPCR. Then, we tested two-step RT-ddPCR and real-time RT-PCR, using clinical samples with low copy numbers. Finally, we used two-step RT-ddPCR to evaluate clinical samples obtained from HPeV3-infected patients with positive serum but negative CSF, as determined by real-time RT-PCR.
Results: Two-step RT-ddPCR was less variable and more specific than one-step RT-ddPCR. Two-step RT-ddPCR detected HPeV3 RNA in all six CSF samples; four samples (67%) were reproducibly positive and the other two samples (33%) were positive at least once in four replicates. Finally, no nonspecific droplet was positive by two-step RT-ddPCR.
Conclusions: Two-step RT-ddPCR may enhance the rate of HPeV3 RNA detection from samples with low viral loads, thereby improving diagnosis and management of HPeV3-infected patients. (C) 2016 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jcv.2016.09.009

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Clinical Characterization of Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia 査読

Takuya Konno, Kunihiro Yoshida, Toshiki Mizuno, Toshitaka Kawarai, Masayoshi Tada, Hiroaki Nozaki, Shu-ichi Ikeda, Masatoyo Nishizawa, Osamu Onodera, Zbigniew K. Wszolek, Takeshi Ikeuchi

ANNALS OF NEUROLOGY   80   S194 - S194   2016年10月

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記述言語：英語   出版者・発行元：WILEY-BLACKWELL  

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Characteristic Microglial Features in Patients with Hereditary Diffuse Leukoencephalopathy with Spheroids 査読

Mari Tada, Takuya Konno, Masayoshi Tada, Toshiyuki Tezuka, Takeshi Miura, Naomi Mezaki, Ken-ichi Okazaki, Musashi Arakawa, Kyoko Itoh, Toru Yamamoto, Hideaki Yokoo, Nobuaki Yoshikura, Kenji Ishihara, Masao Horie, Hirohide Takebayashi, Yasuko Toyoshima, Makoto Naito, Osamu Onodera, Masatoyo Nishizawa, Hitoshi Takahashi, Takeshi Ikeuchi, Akiyoshi Kakita

ANNALS OF NEUROLOGY   80 ( 4 )   554 - 565   2016年10月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Objective: To clarify the histopathological alterations of microglia in the brains of patients with hereditary diffuse leukoencephalopathy with spheroids (HDLS) caused by mutations of the gene encoding the colony stimulating factor-1 receptor (CSF-1R).
Methods: We examined 5 autopsied brains and 1 biopsy specimen from a total of 6 patients with CSF-1R mutations. Detailed immunohistochemical, biochemical, and ultrastructural features of microglia were examined, and quantitative analyses were performed.
Results: In layers 3 to 4 of the frontal cortex in HDLS brains, microglia showed relatively uniform and delicate morphology, with thin and winding processes accompanying knotlike structures, and significantly smaller areas of Iba1 immunoreactivity and lower numbers of Iba1-positive cells were evident in comparison with control brains. On the other hand, in layers 5 to 6 and the underlying white matter, microglia were distributed unevenly; that is, in some areas they had accumulated densely, whereas in others they were scattered. Immunoblot analyses of microglia-associated proteins, including CD11b and DAP12, revealed that HDLS brains had significantly lower amounts of these proteins than diseased controls, although Ki-67-positive proliferative microglia were not reduced. Ultrastructurally, the microglial cytoplasm and processes in HDLS showed vesiculation of the rough endoplasmic reticulum and disaggregated polyribosomes, indicating depression of protein synthesis. On the other hand, macrophages were immunonegative for GLUT-5 or P2ry12, indicating that they were derived from bone marrow.
Interpretation: The pathogenesis of HDLS seems to be associated with microglial vulnerability and morphological alterations.

DOI： 10.1002/ana.24754

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Clinicopathological characteristics of patients with amyotrophic lateral sclerosis resulting in a totally locked-in state (communication Stage V) 査読

Kentaro Hayashi, Yoko Mochizuki, Ryoko Takeuchi, Toshio Shimizu, Masahiro Nagao, Kazuhiko Watabe, Nobutaka Arai, Kiyomitsu Oyanagi, Osamu Onodera, Masaharu Hayashi, Hitoshi Takahashi, Akiyoshi Kakita, Eiji Isozaki

ACTA NEUROPATHOLOGICA COMMUNICATIONS   4 ( 1 )   107   2016年9月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BIOMED CENTRAL LTD  

In the present study, we performed a comprehensive analysis to clarify the clinicopathological characteristics of patients with amyotrophic lateral sclerosis (ALS) that had progressed to result in a totally locked-in state (communication Stage V), in which all voluntary movements are lost and communication is impossible. In 11 patients, six had phosphorylated TAR DNA-binding protein 43 (pTDP-43)-immunoreactive (ir) neuronal cytoplasmic inclusions (NCI), two had fused in sarcoma (FUS)-ir NCI, and three had copper/zinc superoxide dismutase (SOD1)-ir NCI. The time from ALS onset to the need for tracheostomy invasive ventilation was less than 24 months in ten patients. Regardless of accumulated protein, all the patients showed common lesions in the pallido-nigro-luysian system, brainstem reticular formation, and cerebellar efferent system, in addition to motor neurons. In patients with pTDP-43-ir NCI, patients with NCI in the hippocampal dentate granule neurons (DG) showed a neuronal loss in the cerebral cortex, and patients without NCI in DG showed a preserved cerebral cortex. By contrast, in patients with FUS-ir NCI, patients with NCI in DG showed a preserved cerebral cortex and patients without NCI in DG showed marked cerebral degeneration. The cerebral cortex of patients with SOD1-ir NCI was preserved. Together, these findings suggest that lesions of the cerebrum are probably not necessary for progression to Stage V. In conclusion, patients with ALS that had progressed to result in communication Stage V showed rapidly-progressed symptoms, and their common lesions could cause the manifestations of communication Stage V.

DOI： 10.1186/s40478-016-0379-3

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Heterogeneity of cerebral TDP-43 pathology in sporadic amyotrophic lateral sclerosis: Evidence for clinico-pathologic subtypes 査読

Ryoko Takeuchi, Mari Tada, Atsushi Shiga, Yasuko Toyoshima, Takuya Konno, Tomoe Sato, Hiroaki Nozaki, Taisuke Kato, Masao Horie, Hiroshi Shimizu, Hirohide Takebayashi, Osamu Onodera, Masatoyo Nishizawa, Akiyoshi Kakita, Hitoshi Takahashi

ACTA NEUROPATHOLOGICA COMMUNICATIONS   4 ( 1 )   61   2016年6月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BIOMED CENTRAL LTD  

Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are types of major TDP-43 (43-kDa TAR DNA-binding protein) proteinopathy. Cortical TDP-43 pathology has been analyzed in detail in cases of FTLD-TDP, but is still unclear in cases of ALS. We attempted to clarify the cortical and subcortical TDP-43 pathology in Japanese cases of sporadic ALS (n = 96) using an antibody specific to phosphorylated TDP-43 (pTDP-43). The cases were divided into two groups: those without pTDP-43-positive neuronal cytoplasmic inclusions in the hippocampal dentate granule cells (Type 1, n = 63), and those with such inclusions (Type 2, n = 33). Furthermore, the Type 2 cases were divided into two subgroups based on semi-quantitative estimation of pTDP-43-positive dystrophic neurites (DNs) in the temporal neocortex: Type 2a (accompanied by no or few DNs, n = 22) and Type 2b (accompanied by abundant DNs, n = 11). Clinico-pathologic analysis revealed that cognitive impairment was a feature in patients with Type 2a and Type 2b, but not in those with Type 1, and that importantly, Type 2b is a distinct subtype characterized by a poor prognosis despite the less severe loss of lower motor neurons, the unusual subcortical dendrospinal pTDP-43 pathology, and more prominent glial involvement in cortical pTDP-43 pathology than other two groups. Considering the patient survival time and severity of motor neuron loss in each group, transition from Type 1 to Type 2, or from Type 2a to Type 2b during the disease course appeared unlikely. Therefore, each of these three groups was regarded as an independent subtype.

DOI： 10.1186/s40478-016-0335-2

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Proposed Diagnostic Criteria for Adult-onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia 査読

Takuya Konno, Kunihiro Yoshida, Toshiki Mizuno, Toshitaka Kawarai, Masayoshi Tada, Hiroaki Nozaki, Shu-Ichi Ikeda, Masatoyo Nishizawa, Osamu Onodera, Zbigniew Wszolek, Takeshi Ikeuchi

NEUROLOGY   86   2016年4月

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記述言語：英語   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

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Roles of inositol 1,4,5-trisphosphate receptors in spinocerebellar ataxias 査読

Masayoshi Tada, Masatoyo Nishizawa, Osamu Onodera

NEUROCHEMISTRY INTERNATIONAL   94   1 - 8   2016年3月

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記述言語：英語   出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD  

Modulation of the intracellular calcium concentration is a ubiquitous signaling system involved in the control of numerous biological processes in a wide variety of cells. Inositol 1,4,5-trisphosphate (IP3) receptors (IP(3)Rs), which act as calcium release channels in the ER membrane, play a key role in the regulation of intracellular calcium concentration. IP3R type 1 (IP(3)R1) is the major neuronal IP3R isoform in the central nervous system and particularly abundant in cerebellar Purkinje cells. Heterozygous deletions or missense mutations in ITPR1, which encodes IP(3)R1, result in autosomal dominantly inherited spinocerebellar ataxias (SCAs), including SCA types 15 (SCA15) and 29 (SCA29). In addition, homozygous missense mutations in carbonic anhydrase-related protein VIII (CARP), which suppresses the ability of IP3 to bind to IP(3)R1, cause a recessively inherited ataxia with mild cognitive impairment with/without quadrupedal gait. Moreover, cytosolic calcium overload with excessive IP(3)R1 activity has been implicated in the pathogenesis of other SCAs, including SCA types 2 (SCA2) and 3 (SCA3). These facts indicate that dysregulation of IP3R-mediated calcium signaling is linked to the pathogenesis of SCAs. Here, we focus on the molecular basis of SCA15 and SCA29, which are caused by mutations in ITPR1. In addition, we discuss other SCAs whose pathogenesis may be linked to aberrant activation of IP3R-mediated Ca2+ signaling. (C) 2016 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.neuint.2016.01.007

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Pathological and Clinical Spectrum of Progressive Supranuclear Palsy: With Special Reference to Astrocytic Tau Pathology 査読

Yuichi Yokoyama, Yasuko Toyoshima, Atsushi Shiga, Mari Tada, Hideaki Kitamura, Kazuko Hasegawa, Osamu Onodera, Takeshi Ikeuchi, Toshiyuki Someya, Masatoyo Nishizawa, Akiyoshi Kakita, Hitoshi Takahashi

BRAIN PATHOLOGY   26 ( 2 )   155 - 166   2016年3月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Progressive supranuclear palsy (PSP) is a four-repeat tauopathy with tau-positive, argyrophilic tuft-shaped astrocytes (TAs). We performed a pathological and clinical investigation in 40 consecutive autopsied Japanese patients with pathological diagnoses of PSP or PSP-like disease. Unequivocal TAs were present in 22 cases, all of which were confirmed to be PSP. Such TAs were hardly detected in the other 18 cases, which instead exhibited tau-positive, argyrophilic astrocytes, appearing as comparatively small clusters with central nuclei of irregularly shaped, coarse structures (equivocal TAs). Cluster analysis of the distribution pattern of tau-related pathology for these 18 cases identified two subgroups, pallido-nigro-luysian atrophy (PNLA) Type 1 (n=9) and Type 2 (n=9), the former being distinguished from the latter by the presence of tau-related lesions in the motor cortex, pontine nucleus and cerebellar dentate nucleus in addition to the severely affected PNL system. The duration from symptom onset until becoming wheelchair-bound was significantly longer in PNLAType 1. Immunoblotting of samples from the three disease conditions revealed band patterns of low-molecular-mass tau fragments at approximate to 35kDa. These findings shed further light on the wide pathological and clinical spectrum of four-repeat tauopathy, representing PSP in the broad sense rather than classical PSP.

DOI： 10.1111/bpa.12265

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