研究者詳細 - 小野寺　理

論文 - 小野寺　理

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Inherited C-terminal TREX1 variants disrupt homology-directed repair to cause senescence and DNA damage phenotypes in Drosophila, mice, and humans

Samuel D. Chauvin, Shoichiro Ando, Joe A. Holley, Atsushi Sugie, Fang R. Zhao, Subhajit Poddar, Rei Kato, Cathrine A. Miner, Yohei Nitta, Siddharth R. Krishnamurthy, Rie Saito, Yue Ning, Yuya Hatano, Sho Kitahara, Shin Koide, W. Alexander Stinson, Jiayuan Fu, Nehalee Surve, Lindsay Kumble, Wei Qian, Oleksiy Polishchuk, Prabhakar S. Andhey, Cindy Chiang, Guanqun Liu, Ludovic Colombeau, Raphaël Rodriguez, Nicolas Manel, Akiyoshi Kakita, Maxim N. Artyomov, David C. Schultz, P. Toby Coates, Elisha D. O. Roberson, Yasmine Belkaid, Roger A. Greenberg, Sara Cherry, Michaela U. Gack, Tristan Hardy, Osamu Onodera, Taisuke Kato, Jonathan J. Miner

Nature Communications 15 ( 1 ) 2024年6月

掲載種別：研究論文（学術雑誌）出版者・発行元：Springer Science and Business Media LLC

Abstract

Age-related microangiopathy, also known as small vessel disease (SVD), causes damage to the brain, retina, liver, and kidney. Based on the DNA damage theory of aging, we reasoned that genomic instability may underlie an SVD caused by dominant C-terminal variants in TREX1, the most abundant 3′−5′ DNA exonuclease in mammals. C-terminal TREX1 variants cause an adult-onset SVD known as retinal vasculopathy with cerebral leukoencephalopathy (RVCL or RVCL-S). In RVCL, an aberrant, C-terminally truncated TREX1 mislocalizes to the nucleus due to deletion of its ER-anchoring domain. Since RVCL pathology mimics that of radiation injury, we reasoned that nuclear TREX1 would cause DNA damage. Here, we show that RVCL-associated TREX1 variants trigger DNA damage in humans, mice, and Drosophila, and that cells expressing RVCL mutant TREX1 are more vulnerable to DNA damage induced by chemotherapy and cytokines that up-regulate TREX1, leading to depletion of TREX1-high cells in RVCL mice. RVCL-associated TREX1 mutants inhibit homology-directed repair (HDR), causing DNA deletions and vulnerablility to PARP inhibitors. In women with RVCL, we observe early-onset breast cancer, similar to patients with BRCA1/2 variants. Our results provide a mechanistic basis linking aberrant TREX1 activity to the DNA damage theory of aging, premature senescence, and microvascular disease.

DOI： 10.1038/s41467-024-49066-7

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その他リンク： https://www.nature.com/articles/s41467-024-49066-7

TDP-43 differentially propagates to induce antero- and retrograde degeneration in the corticospinal circuits in mouse focal ALS models. 国際誌

Shintaro Tsuboguchi, Yuka Nakamura, Tomohiko Ishihara, Taisuke Kato, Tokiharu Sato, Akihide Koyama, Hideki Mori, Yuka Koike, Osamu Onodera, Masaki Ueno

Acta neuropathologica 2023年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by TDP-43 inclusions in the cortical and spinal motor neurons. It remains unknown whether and how pathogenic TDP-43 spreads across neural connections to progress degenerative processes in the cortico-spinal motor circuitry. Here we established novel mouse ALS models that initially induced mutant TDP-43 inclusions in specific neuronal or cell types in the motor circuits, and investigated whether TDP-43 and relevant pathological processes spread across neuronal or cellular connections. We first developed ALS models that primarily induced TDP-43 inclusions in the corticospinal neurons, spinal motor neurons, or forelimb skeletal muscle, by using adeno-associated virus (AAV) expressing mutant TDP-43. We found that TDP-43 induced in the corticospinal neurons was transported along the axons anterogradely and transferred to the oligodendrocytes along the corticospinal tract (CST), coinciding with mild axon degeneration. In contrast, TDP-43 introduced in the spinal motor neurons did not spread retrogradely to the cortical or spinal neurons; however, it induced an extreme loss of spinal motor neurons and subsequent degeneration of neighboring spinal neurons, suggesting a degenerative propagation in a retrograde manner in the spinal cord. The intraspinal degeneration further led to severe muscle atrophy. Finally, TDP-43 induced in the skeletal muscle did not propagate pathological events to spinal neurons retrogradely. Our data revealed that mutant TDP-43 spread across neuro-glial connections anterogradely in the corticospinal pathway, whereas it exhibited different retrograde degenerative properties in the spinal circuits. This suggests that pathogenic TDP-43 may induce distinct antero- and retrograde mechanisms of degeneration in the motor system in ALS.

DOI： 10.1007/s00401-023-02615-8

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Phosphorylation of α-synuclein at T64 results in distinct oligomers and exerts toxicity in models of Parkinson's disease. 国際誌

Hideaki Matsui, Shinji Ito, Hideki Matsui, Junko Ito, Ramil Gabdulkhaev, Mika Hirose, Tomoyuki Yamanaka, Akihide Koyama, Taisuke Kato, Maiko Tanaka, Norihito Uemura, Noriko Matsui, Sachiko Hirokawa, Maki Yoshihama, Aki Shimozawa, Shin-Ichiro Kubo, Kenji Iwasaki, Masato Hasegawa, Ryosuke Takahashi, Keisuke Hirai, Akiyoshi Kakita, Osamu Onodera

Proceedings of the National Academy of Sciences of the United States of America 120 ( 23 ) e2214652120 2023年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

α-Synuclein accumulates in Lewy bodies, and this accumulation is a pathological hallmark of Parkinson's disease (PD). Previous studies have indicated a causal role of α-synuclein in the pathogenesis of PD. However, the molecular and cellular mechanisms of α-synuclein toxicity remain elusive. Here, we describe a novel phosphorylation site of α-synuclein at T64 and the detailed characteristics of this post-translational modification. T64 phosphorylation was enhanced in both PD models and human PD brains. T64D phosphomimetic mutation led to distinct oligomer formation, and the structure of the oligomer was similar to that of α-synuclein oligomer with A53T mutation. Such phosphomimetic mutation induced mitochondrial dysfunction, lysosomal disorder, and cell death in cells and neurodegeneration in vivo, indicating a pathogenic role of α-synuclein phosphorylation at T64 in PD.

DOI： 10.1073/pnas.2214652120

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Candesartan prevents arteriopathy progression in cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy model. 査読国際誌

Taisuke Kato, Ri-Ichiroh Manabe, Hironaka Igarashi, Fuyuki Kametani, Sachiko Hirokawa, Yumi Sekine, Natsumi Fujita, Satoshi Saito, Yusuke Kawashima, Yuya Hatano, Shoichiro Ando, Hiroaki Nozaki, Akihiro Sugai, Masahiro Uemura, Masaki Fukunaga, Toshiya Sato, Akihide Koyama, Rie Saito, Atsushi Sugie, Yasuko Toyoshima, Hirotoshi Kawata, Shigeo Murayama, Masaki Matsumoto, Akiyoshi Kakita, Masato Hasegawa, Masafumi Ihara, Masato Kanazawa, Masatoyo Nishizawa, Shoji Tsuji, Osamu Onodera

The Journal of clinical investigation 131 ( 22 ) 2021年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

Cerebral small vessel disease (CSVD) causes dementia and gait disturbance due to arteriopathy. Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a hereditary form of CSVD caused by loss of high-temperature requirement A1 (HTRA1) serine protease activity. In CARASIL, arteriopathy causes intimal thickening, smooth muscle cell (SMC) degeneration, elastic lamina splitting, and vasodilation. The molecular mechanisms were proposed to involve the accumulation of matrisome proteins as substrates or abnormalities in transforming growth factor β (TGF-β) signaling. Here, we show that HTRA1-/- mice exhibited features of CARASIL-associated arteriopathy: intimal thickening, abnormal elastic lamina, and vasodilation. In addition, the mice exhibited reduced distensibility of the cerebral arteries and blood flow in the cerebral cortex. In the thickened intima, matrisome proteins, including the hub protein fibronectin (FN) and latent TGF-β binding protein 4 (LTBP-4), which are substrates of HTRA1, accumulated. Candesartan treatment alleviated matrisome protein accumulation and normalized the vascular distensibility and cerebral blood flow. Furthermore, candesartan reduced the mRNA expression of Fn1, Ltbp-4, and Adamtsl2, which are involved in forming the extracellular matrix network. Our results indicate that these accumulated matrisome proteins may be potential therapeutic targets for arteriopathy in CARASIL.

DOI： 10.1172/JCI140555

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Age-related demethylation of the TDP-43 autoregulatory region in the human motor cortex. 国際誌

Yuka Koike, Akihiro Sugai, Norikazu Hara, Junko Ito, Akio Yokoseki, Tomohiko Ishihara, Takuma Yamagishi, Shintaro Tsuboguchi, Mari Tada, Takeshi Ikeuchi, Akiyoshi Kakita, Osamu Onodera

Communications biology 4 ( 1 ) 1107 - 1107 2021年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

In amyotrophic lateral sclerosis (ALS), TAR DNA-binding protein 43 (TDP-43), which is encoded by TARDBP, forms aggregates in the motor cortex. This aggregate formation may be triggered by an increase in the TDP-43 level with aging. However, the amount of TDP-43 is autoregulated by alternative splicing of the TARDBP 3'UTR, and how this autoregulation is affected by aging remains to be elucidated. We found that DNA demethylation in the autoregulatory region in the TARDBP 3'UTR reduced alternative splicing and increased TARDBP mRNA expression. Furthermore, in the human motor cortex, we found that this region was demethylated with aging, resulting in increased expression of TARDBP mRNA. The acceleration of DNA demethylation in the motor cortex was associated with the age of ALS onset. In summary, the dysregulation of TDP-43 autoregulation by age-related DNA demethylation in the motor cortex may explain the contribution of aging and motor system selectivity in ALS.

DOI： 10.1038/s42003-021-02621-0

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

Seiichi Nagano, Junki Jinno, Rehab F Abdelhamid, Yinshi Jin, Megumi Shibata, Shohei Watanabe, Sachiko Hirokawa, Masatoyo Nishizawa, Kenji Sakimura, Osamu Onodera, Hironori Okada, Takashi Okada, Yuko Saito, Junko Takahashi-Fujigasaki, Shigeo Murayama, Shuji Wakatsuki, Hideki Mochizuki, Toshiyuki Araki

Acta neuropathologica 140 ( 5 ) 695 - 713 2020年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Springer Science and Business Media LLC

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.

DOI： 10.1007/s00401-020-02205-y

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その他リンク： http://link.springer.com/article/10.1007/s00401-020-02205-y/fulltext.html

Toward allele-specific targeting therapy and pharmacodynamic marker for spinocerebellar ataxia type 3. 査読国際誌

Mercedes Prudencio, Hector Garcia-Moreno, Karen R Jansen-West, Rana Hanna Al-Shaikh, Tania F Gendron, Michael G Heckman, Matthew R Spiegel, Yari Carlomagno, Lillian M Daughrity, Yuping Song, Judith A Dunmore, Natalie Byron, Björn Oskarsson, Katharine A Nicholson, Nathan P Staff, Sorina Gorcenco, Andreas Puschmann, João Lemos, Cristina Januário, Mark S LeDoux, Joseph H Friedman, James Polke, Robin Labrum, Vikram Shakkottai, Hayley S McLoughlin, Henry L Paulson, Takuya Konno, Osamu Onodera, Takeshi Ikeuchi, Mari Tada, Akiyoshi Kakita, John D Fryer, Christin Karremo, Inês Gomes, John N Caviness, Mark R Pittelkow, Jan Aasly, Ronald F Pfeiffer, Venka Veerappan, Eric R Eggenberger, William D Freeman, Josephine F Huang, Ryan J Uitti, Klaas J Wierenga, Iris V Marin Collazo, Philip W Tipton, Jay A van Gerpen, Marka van Blitterswijk, Guojun Bu, Zbigniew K Wszolek, Paola Giunti, Leonard Petrucelli

Science translational medicine 12 ( 566 ) 2020年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

Spinocerebellar ataxia type 3 (SCA3), caused by a CAG repeat expansion in the ataxin-3 gene (ATXN3), is characterized by neuronal polyglutamine (polyQ) ATXN3 protein aggregates. Although there is no cure for SCA3, gene-silencing approaches to reduce toxic polyQ ATXN3 showed promise in preclinical models. However, a major limitation in translating putative treatments for this rare disease to the clinic is the lack of pharmacodynamic markers for use in clinical trials. Here, we developed an immunoassay that readily detects polyQ ATXN3 proteins in human biological fluids and discriminates patients with SCA3 from healthy controls and individuals with other ataxias. We show that polyQ ATXN3 serves as a marker of target engagement in human fibroblasts, which may bode well for its use in clinical trials. Last, we identified a single-nucleotide polymorphism that strongly associates with the expanded allele, thus providing an exciting drug target to abrogate detrimental events initiated by mutant ATXN3. Gene-silencing strategies for several repeat diseases are well under way, and our results are expected to improve clinical trial preparedness for SCA3 therapies.

DOI： 10.1126/scitranslmed.abb7086

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Arginine is a disease modifier for polyQ disease models that stabilizes polyQ protein conformation. 査読国際誌

Eiko N Minakawa, Helena Akiko Popiel, Masayoshi Tada, Toshiaki Takahashi, Hiroshi Yamane, Yuji Saitoh, Yasuo Takahashi, Daisaku Ozawa, Akiko Takeda, Toshihide Takeuchi, Yuma Okamoto, Kazuhiro Yamamoto, Mari Suzuki, Hiromi Fujita, Chiyomi Ito, Hiroko Yagihara, Yuko Saito, Kei Watase, Hiroaki Adachi, Masahisa Katsuno, Hideki Mochizuki, Kentaro Shiraki, Gen Sobue, Tatsushi Toda, Keiji Wada, Osamu Onodera, Yoshitaka Nagai

Brain : a journal of neurology 143 ( 6 ) 1811 - 1825 2020年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Oxford University Press (OUP)

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.

DOI： 10.1093/brain/awaa115

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Effect of rovatirelin in patients with cerebellar ataxia: two randomised double-blind placebo-controlled phase 3 trials. 査読国際誌

Masatoyo Nishizawa, Osamu Onodera, Akihiro Hirakawa, Yoshitaka Shimizu, Masayuki Yamada

Journal of neurology, neurosurgery, and psychiatry 91 ( 3 ) 254 - 262 2020年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVE: To investigate the efficacy of rovatirelin, a thyrotropin-releasing hormone analogue, for ataxias in patients with spinocerebellar degeneration (SCD). METHODS: Two multicentre, randomised, double-blind, placebo-controlled phase 3 studies (KPS1301, KPS1305) enrolled patients with predominant cerebellar ataxia, including SCA6, SCA31 or cortical cerebellar atrophy. KPS1301 enrolled patients with truncal ataxia and KPS1305 enrolled patients with truncal and limb ataxia. Each study included 4 weeks of pretreatment, a 28-week or 24-week treatment period and 4 weeks of follow-up. Patients were randomised (1:1:1) to rovatirelin (1.6 or 2.4 mg) or placebo in KPS1301, and randomised (1:1) to rovatirelin 2.4 mg or placebo in KPS1305. The primary endpoint was change in Scale for the Assessment and Rating of Ataxia (SARA) total scores. Pooled analysis was performed in patients who met the SARA recruitment criteria of KPS1305. RESULTS: From October 2013 to May 2014, KPS1301 enrolled 411 patients; 374 were randomised to rovatirelin 1.6 mg (n=125), rovatirelin 2.4 mg (n=126) or placebo (n=123). From November 2016 to August 2017, KPS1305 enrolled 241 patients; 203 were randomised to rovatirelin 2.4 mg (n=101) or placebo (n=102). The primary endpoint showed no significant difference between rovatirelin and placebo in these two studies. In the pooled analysis (n=278), the difference between rovatirelin 2.4 mg (n=140) and placebo (n=138) was -0.61 (-1.64 vs -1.03; 95% CI -1.16 to -0.06; p=0.029) in the adjusted mean change in the SARA total score. CONCLUSIONS: Rovatirelin is a potentially effective treatment option for SCD. TRIAL REGISTRATION NUMBER: NCT01970098; NCT02889302.

DOI： 10.1136/jnnp-2019-322168

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Amyotrophic Lateral Sclerosis with Pallidonigroluysian Degeneration: A Clinicopathological Study. 査読国際誌

Junko Ito, Hiroshi Shimizu, Kentaro Ohta, Jiro Idezuka, Hajime Tanaka, Hiroshi Kondo, Takashi Nakajima, Hitoshi Takahashi, Kohei Akazawa, Osamu Onodera, Akiyoshi Kakita

Annals of neurology 87 ( 2 ) 302 - 312 2020年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVE: The pallidonigroluysian (PNL) system, the primary component of corticosubcortical circuits, is generally spared in amyotrophic lateral sclerosis (ALS). We evaluated the clinicopathological features of an unusual form of ALS with PNL degeneration (PNLD) and assessed whether ALS with PNLD represents a distinct ALS subtype. METHODS: From a cohort of 97 autopsied cases of sporadic ALS with phosphorylated 43kDa TAR DNA-binding protein (TDP-43) inclusions, we selected those with PNLD and analyzed their clinicopathological features. RESULTS: Eleven cases (11%) that showed PNLD were divided into 2 subtypes depending on the lesion distribution: (1) extensive type (n = 6), showing widespread TDP-43 pathology and multisystem degeneration, both involving the PNL system; and (2) limited type (n = 5), showing selective PNL and motor system involvement, thus being unclassifiable in terms of Brettschneider's staging or Nishihira's typing of ALS. The limited type showed a younger age at onset and predominant PNLD that accounted for the early development of extrapyramidal signs. The limited type exhibited the heaviest pathology in the subthalamus and external globus pallidus, suggesting that TDP-43 inclusions propagated via indirect or hyperdirect pathways, unlike ALS without PNLD, where the direct pathway is considered to convey TDP-43 aggregates from the cerebral cortex to the substantia nigra. INTERPRETATION: The PNL system can be involved in the disease process of ALS, either nonselectively as part of multisystem degeneration, or selectively. ALS with selective involvement of the PNL and motor systems exhibits unique clinicopathological features and TDP-43 propagation routes, thus representing a distinct subtype of ALS. ANN NEUROL 2020;87:302-312.

DOI： 10.1002/ana.25652

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HTRA1-Related Cerebral Small Vessel Disease: A Review of the Literature. 査読国際誌

Masahiro Uemura, Hiroaki Nozaki, Taisuke Kato, Akihide Koyama, Naoko Sakai, Shoichiro Ando, Masato Kanazawa, Nozomi Hishikawa, Yoshinori Nishimoto, Kiran Polavarapu, Atchayaram Nalini, Akira Hanazono, Daisuke Kuzume, Akihiro Shindo, Mohammad El-Ghanem, Arata Abe, Aki Sato, Mari Yoshida, Takeshi Ikeuchi, Ikuko Mizuta, Toshiki Mizuno, Osamu Onodera

Frontiers in neurology 11 545 - 545 2020年

記述言語：英語掲載種別：研究論文（学術雑誌）

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is clinically characterized by early-onset dementia, stroke, spondylosis deformans, and alopecia. In CARASIL cases, brain magnetic resonance imaging reveals severe white matter hyperintensities (WMHs), lacunar infarctions, and microbleeds. CARASIL is caused by a homozygous mutation in high-temperature requirement A serine peptidase 1 (HTRA1). Recently, it was reported that several heterozygous mutations in HTRA1 also cause cerebral small vessel disease (CSVD). Although patients with heterozygous HTRA1-related CSVD (symptomatic carriers) are reported to have a milder form of CARASIL, little is known about the clinical and genetic differences between the two diseases. Given this gap in the literature, we collected clinical information on HTRA1-related CSVD from a review of the literature to help clarify the differences between symptomatic carriers and CARASIL and the features of both diseases. Forty-six symptomatic carriers and 28 patients with CARASIL were investigated. Twenty-eight mutations in symptomatic carriers and 22 mutations in CARASIL were identified. Missense mutations in symptomatic carriers are more frequently identified in the linker or loop 3 (L3)/loop D (LD) domains, which are critical sites in activating protease activity. The ages at onset of neurological symptoms/signs were significantly higher in symptomatic carriers than in CARASIL, and the frequency of characteristic extraneurological findings and confluent WMHs were significantly higher in CARASIL than in symptomatic carriers. As previously reported, heterozygous HTRA1-related CSVD has a milder clinical presentation of CARASIL. It seems that haploinsufficiency can cause CSVD among symptomatic carriers according to the several patients with heterozygous nonsense/frameshift mutations. However, the differing locations of mutations found in the two diseases indicate that distinct molecular mechanisms influence the development of CSVD in patients with HTRA1-related CSVD. These findings further support continued careful examination of the pathogenicity of mutations located outside the linker or LD/L3 domain in symptomatic carriers.

DOI： 10.3389/fneur.2020.00545

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Non-genetically modified models exhibit TARDBP mRNA increase due to perturbed TDP-43 autoregulation. 査読国際誌

Akihiro Sugai, Taisuke Kato, Akihide Koyama, Yuka Koike, Takuya Konno, Tomohiko Ishihara, Osamu Onodera

Neurobiology of disease 130 104534 - 104534 2019年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by accumulation of fragmented insoluble TDP-43 and loss of TDP-43 from the nucleus. Increased expression of exogenous TARDBP (encoding TDP-43) induces TDP-43 pathology and cytotoxicity, suggesting the involvement of aberrant expression of TDP-43 in the pathogenesis of ALS. In normal conditions, however, the amount of TDP-43 is tightly regulated by the autoregulatory mechanism involving alternative splicing of TARDBP mRNA. To investigate the influence of autoregulation dysfunction, we inhibited the splicing of cryptic intron 6 using antisense oligonucleotides in vivo. This inhibition doubled the Tardbp mRNA expression, increased the fragmented insoluble TDP-43, and reduced the number of motor neurons in the mouse spinal cord. In human induced pluripotent stem cell-derived neurons, the splicing inhibition of intron 6 increased TARDBP mRNA and decreased nuclear TDP-43. These non-genetically modified models exhibiting rise in the TARDBP mRNA levels suggest that TDP-43 autoregulation turbulence might be linked to the pathogenesis of ALS.

DOI： 10.1016/j.nbd.2019.104534

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Retinal Vasculopathy With Cerebral Leukodystrophy: Clinicopathologic Features of an Autopsied Patient With a Heterozygous TREX 1 Mutation. 査読国際誌

Rie Saito, Hiroaki Nozaki, Taisuke Kato, Yasuko Toyoshima, Hajime Tanaka, Yutaka Tsubata, Tetsuo Morioka, Yoh Horikawa, Kiyomitsu Oyanagi, Takashi Morita, Osamu Onodera, Akiyoshi Kakita

Journal of neuropathology and experimental neurology 78 ( 2 ) 181 - 186 2019年2月

記述言語：英語

Retinal vasculopathy with cerebral leukodystrophy (RVCL) is an autosomal-dominant disorder involving the cerebral, retinal, renal, and other systemic microvessels due to frameshift mutations in the TREX1 gene. Under physiological conditions, the TREX1 protein is localized in the cellular cytoplasm and perinuclear area, but translocates into the nucleus in response to oxidative DNA damage. It has been speculated that aberrant localization of the protein may be associated with systemic microangiopathy in patients with RVCL. However, cellular expression of TREX1 in the brain and visceral organs of patients with RVCL has been unclear. Here, we report the clinicopathologic features of an autopsied patient with a heterozygous T249fs mutation in TREX1. The patient showed the clinical phenotype of vasculopathy with retinopathy, nephropathy, and stroke. CT with contrast enhancement demonstrated a tumorous lesion in the subcortical white matter. Histologically, the lesion consisted of confluent foci of necrosis with calcification and fibrous thickening of small vessel walls. TREX1 immunohistochemistry demonstrated positivity in the nuclei of cells in the CNS and visceral organs, indicating aberrant localization of the truncated protein, and the expression was remarkable in oligodendrocytes within the lesion, suggesting possible involvement of the protein in the pathomechanism of vasculopathy leading to white matter degeneration.

DOI： 10.1093/jnen/nly115

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HTRA1 Mutations Identified in Symptomatic Carriers Have the Property of Interfering the Trimer-Dependent Activation Cascade. 査読国際誌

Masahiro Uemura, Hiroaki Nozaki, Akihide Koyama, Naoko Sakai, Shoichiro Ando, Masato Kanazawa, Taisuke Kato, Osamu Onodera

Frontiers in neurology 10 693 - 693 2019年

記述言語：英語掲載種別：研究論文（学術雑誌）

Background: Mutations in the high-temperature requirement A serine peptidase 1 (HTRA1) cause cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). Most carriers for HTRA1 mutations are asymptomatic, but more than 10 mutations have been reported in symptomatic carriers. The molecular differences between the mutations identified in symptomatic carriers and mutations identified only in CARASIL patients are unclear. HTRA1 is a serine protease that forms homotrimers, with each HTRA1 subunit activating the adjacent HTRA1 via the sensor domain of loop 3 (L3) and the activation domain of loop D (LD). Previously, we analyzed four HTRA1 mutant proteins identified in symptomatic carriers and found that they were unable to form trimers or had mutations in the LD or L3 domain. The mutant HTRA1s with these properties are presumed to inhibit trimer-dependent activation cascade. Indeed, these mutant HTRA1s inhibited wild-type (WT) protease activity. In this study, we further analyzed 15 missense HTRA1s to clarify the molecular character of mutant HTRA1s identified in symptomatic carriers. Methods: We analyzed 12 missense HTRA1s identified in symptomatic carriers (hetero-HTRA1) and three missense HTRA1s found only in CARASIL (CARASIL-HTRA1). The protease activity of the purified recombinant mutant HTRA1s was measured using fluorescein isothiocyanate-labeled casein as substrate. Oligomeric structure was evaluated by size-exclusion chromatography. The protease activities of mixtures of WT with each mutant HTRA1 were also measured. Results: Five hetero-HTRA1s had normal protease activity and were excluded from further analysis. Four of the seven hetero-HTRA1s and one of the three CARASIL-HTRA1s were unable to form trimers. The other three hetero-HTRA1s had mutations in the LD domain. Together with our previous work, 10 of 11 hetero-HTRA1s and two of six CARASIL-HTRA1s were either defective in trimerization or had mutations in the LD or L3 domain (P = 0.006). By contrast, eight of 11 hetero-HTRA1s and two of six CARASIL-HTRA1 inhibited WT protease activity (P = 0.162). Conclusions: HTRA1 mutations identified in symptomatic carriers have the property of interfering the trimer-dependent activation cascade of HTRA1.

DOI： 10.3389/fneur.2019.00693

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Robustness and Vulnerability of the Autoregulatory System That Maintains Nuclear TDP-43 Levels: A Trade-off Hypothesis for ALS Pathology Based on in Silico Data. 査読国際誌

Akihiro Sugai, Taisuke Kato, Akihide Koyama, Yuka Koike, Sou Kasahara, Takuya Konno, Tomohiko Ishihara, Osamu Onodera

Frontiers in neuroscience 12 28 - 28 2018年

記述言語：英語掲載種別：研究論文（学術雑誌）

Abnormal accumulation of TAR DNA-binding protein 43 (TDP-43) in the cytoplasm and its disappearance from the nucleus are pathological features of amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) and are directly involved in the pathogenesis of these conditions. TDP-43 is an essential nuclear protein that readily aggregates in a concentration-dependent manner. Therefore, cells must strictly maintain an appropriate amount of nuclear TDP-43. In one relevant maintenance mechanism, TDP-43 binds to its pre-mRNA and promotes alternative splicing, resulting in mRNA degradation via nonsense-mediated mRNA decay. The level of nuclear TDP-43 is tightly regulated by these mechanisms, which control the amount of mRNA that may be translated. Based on the results of previous experiments, we developed an in silico model that mimics the intracellular dynamics of TDP-43 and examined TDP-43 metabolism under various conditions. We discovered an inherent trade-off in this mechanism between transcriptional redundancy, which maintains the robustness of TDP-43 metabolism, and vulnerability to specific interfering factors. These factors include an increased tendency of TDP-43 to aggregate, impaired nuclear-cytoplasmic TDP-43 transport, and a decreased efficiency of degrading abnormal proteins, all of which are functional abnormalities related to the gene that causes familial ALS/FTD. When these conditions continue at a certain intensity, the vulnerability of the autoregulatory machinery becomes apparent over time, and transcriptional redundancy enters a vicious cycle that ultimately results in TDP-43 pathology. The results obtained using this in silico model reveal the difference in TDP-43 metabolism between normal and disease states. Furthermore, using this model, we simulated the effect of a decrease in TDP-43 transcription and found that this decrease improved TDP-43 pathology and suppressed the abnormal propagation of TDP-43. Therefore, we propose a potential therapeutic strategy to suppress transcriptional redundancy, which is the driving force of the pathological condition caused by the specific factors described above, in patients with ALS presenting with TDP-43 pathology. An ALS animal model exhibiting TDP-43 pathology without overexpression of exogenous TDP-43 should be developed to investigate the effect of alleviating the transcriptional redundancy of TARDBP.

DOI： 10.3389/fnins.2018.00028

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Increased cytoplasmic TARDBP mRNA in affected spinal motor neurons in ALS caused by abnormal autoregulation of TDP-43 査読

Akihide Koyama, Akihiro Sugai, Taisuke Kato, Tomohiko Ishihara, Atsushi Shiga, Yasuko Toyoshima, Misaki Koyama, Takuya Konno, Sachiko Hirokawa, Akio Yokoseki, Masatoyo Nishizawa, Akiyoshi Kakita, Hitoshi Takahashi, Osamu Onodera

NUCLEIC ACIDS RESEARCH 44 ( 12 ) 5820 - 5836 2016年7月

Distinct molecular mechanisms of HTRA1 mutants in manifesting heterozygotes with CARASIL. 査読国際誌

Hiroaki Nozaki, Taisuke Kato, Megumi Nihonmatsu, Yohei Saito, Ikuko Mizuta, Tomoko Noda, Ryoko Koike, Kazuhide Miyazaki, Muichi Kaito, Shoichi Ito, Masahiro Makino, Akihide Koyama, Atsushi Shiga, Masahiro Uemura, Yumi Sekine, Ayuka Murakami, Suzuko Moritani, Kenju Hara, Akio Yokoseki, Ryozo Kuwano, Naoto Endo, Takeshi Momotsu, Mari Yoshida, Masatoyo Nishizawa, Toshiki Mizuno, Osamu Onodera

Neurology 86 ( 21 ) 1964 - 74 2016年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVE: To elucidate the molecular mechanism of mutant HTRA1-dependent cerebral small vessel disease in heterozygous individuals. METHODS: We recruited 113 unrelated index patients with clinically diagnosed cerebral small vessel disease. The coding sequences of the HTRA1 gene were analyzed. We evaluated HTRA1 protease activities using casein assays and oligomeric HTRA1 formation using gel filtration chromatography. RESULTS: We found 4 heterozygous missense mutations in the HTRA1 gene (p.G283E, p.P285L, p.R302Q, and p.T319I) in 6 patients from 113 unrelated index patients and in 2 siblings in 2 unrelated families with p.R302Q. The mean age at cognitive impairment onset was 51.1 years. Spondylosis deformans was observed in all cases, whereas alopecia was observed in 3 cases; an autopsied case with p.G283E showed arteriopathy in their cerebral small arteries. These mutant HTRA1s showed markedly decreased protease activities and inhibited wild-type HTRA1 activity, whereas 2 of 3 mutant HTRA1s reported in cerebral autosomal-recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) (A252T and V297M) did not inhibit wild-type HTRA1 activity. Wild-type HTRA1 forms trimers; however, G283E and T319I HTRA1, observed in manifesting heterozygotes, did not form trimers. P285L and R302Q HTRA1s formed trimers, but their mutations were located in domains that are important for trimer-associated HTRA1 activation; in contrast, A252T and V297M HTRA1s, which have been observed in CARASIL, also formed trimers but had mutations outside the domains important for trimer-associated HTRA1 activation. CONCLUSIONS: The mutant HTRA1s observed in manifesting heterozygotes might result in an impaired HTRA1 activation cascade of HTRA1 or be unable to form stable trimers.

DOI： 10.1212/WNL.0000000000002694

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Characteristic features and progression of abnormalities on MRI for CARASIL 査読

Hiroaki Nozaki, Yumi Sekine, Toshio Fukutake, Yoshinori Nishimoto, Yutaka Shimoe, Akiko Shirata, Sohei Yanagawa, Mikio Hirayama, Masato Tamura, Masatoyo Nishizawa, Osamu Onodera

NEUROLOGY 85 ( 5 ) 459 - 463 2015年8月

Decreased number of Gemini of coiled bodies and U12 snRNA level in amyotrophic lateral sclerosis 査読

Tomohiko Ishihara, Yuko Ariizumi, Atsushi Shiga, Taisuke Kato, Chun-Feng Tan, Tatsuya Sato, Yukari Miki, Mariko Yokoo, Takeshi Fujino, Akihide Koyama, Akio Yokoseki, Masatoyo Nishizawa, Akiyoshi Kakita, Hitoshi Takahashi, Osamu Onodera

HUMAN MOLECULAR GENETICS 22 ( 20 ) 4136 - 4147 2013年10月

MRI Features of Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy 査読

Hiroaki Nozaki, Yumi Sekine, Toshio Fukutake, Yoshinori Nishimoto, Mamoru Shibata, Shimoe Yutaka, Akiko Shirata, Sohei Yanagawa, Mikio Hirayama, Kiyomi Yamane, Imaharu Nakano, Norihiro Suzuki, Masatoyo Nishizawa, Osamu Onodera

NEUROLOGY 80 560 - 566 2013年2月

Genotype-phenotype correlations in early onset ataxia with ocular motor apraxia and hypoalbuminaemia 査読

Akio Yokoseki, Tomohiko Ishihara, Akihide Koyama, Atsushi Shiga, Mitsunori Yamada, Chieko Suzuki, Yoshiki Sekijima, Kyoko Maruta, Miyuki Tsuchiya, Hidetoshi Date, Tatsuya Sato, Masayoshi Tada, Takeshi Ikeuchi, Shoji Tsuji, Masatoyo Nishizawa, Osamu Onodera

BRAIN 134 ( Pt 5 ) 1387 - 1399 2011年5月

Cerebral small-vessel disease protein HTRA1 controls the amount of TGF-β1 via cleavage of proTGF-β1. 査読

Shiga A, Nozaki H, Yokoseki A, Nihonmatsu M, Kawata H, Kato T, Koyama A, Arima K, Ikeda M, Katada S, Toyoshima Y, Takahashi H, Tanaka A, Nakano I, Ikeuchi T, Nishizawa M, Onodera O

Human molecular genetics 20 ( 9 ) 1800 - 1810 2011年5月

Polyglutamine Diseases: Where does Toxicity Come from? What is Toxicity? Where are We Going? 査読

Toshiaki Takahashi, Shinichi Katada, Osamu Onodera

JOURNAL OF MOLECULAR CELL BIOLOGY 2 ( 4 ) 180 - 191 2010年8月

Association of HTRA1 Mutations and Familial Ischemic Cerebral Small-Vessel Disease 査読

Kenju Hara, Atsushi Shiga, Toshio Fukutake, Hiroaki Nozaki, Akinori Miyashita, Akio Yokoseki, Hirotoshi Kawata, Akihide Koyama, Kunimasa Arima, Toshiaki Takahashi, Mari Ikeda, Hiroshi Shiota, Masato Tamura, Yutaka Shimoe, Mikio Hirayama, Takayo Arisato, Sohei Yanagawa, Akira Tanaka, Imaharu Nakano, Shu-ichi Ikeda, Yutaka Yoshida, Tadashi Yamamoto, Takeshi Ikeuchi, Ryozo Kuwano, Masatoyo Nishizawa, Shoji Tsuji, Osamu Onodera

NEW ENGLAND JOURNAL OF MEDICINE 360 ( 17 ) 1729 - 1739 2009年4月

TDP-43 mutation in familial amyotrophic lateral sclerosis 査読

Akio Yokoseki, Atsushi Shiga, Chun-Feng Tan, Asako Tagawa, Hiroyuki Kaneko, Akihide Koyama, Hiroto Eguchi, Akira Tsujino, Takeshi Ikeuchi, Akiyoshi Kakita, Koichi Okamoto, Masatoyo Nishizava, Hitoshi Takahashi, Osamu Onodera

ANNALS OF NEUROLOGY 63 ( 4 ) 538 - 542 2008年4月

Soluble polyglutamine oligomers formed prior to inclusion body formation are cytotoxic 査読

Toshiaki Takahashi, Shinya Kikuchi, Shinichi Katada, Yoshitaka Nagai, Masatoyo Nishizawa, Osamu Onodera

HUMAN MOLECULAR GENETICS 17 ( 3 ) 345 - 356 2008年2月

Aprataxin, causative gene product for EAOH/AOA1, repairs DNA single-strand breaks with damaged 3 '-phosphate and 3 '-phosphoglycolate ends 査読

Tetsuya Takahashi, Masayoshi Tada, Shuichi Igarashi, Akihide Koyama, Hidetoshi Date, Akio Yokoseki, Atsushi Shiga, Yutaka Yoshida, Shoji Tsuji, Masatoyo Nishizawa, Osamu Onodera

NUCLEIC ACIDS RESEARCH 35 ( 11 ) 3797 - 3809 2007年6月

Early development of autonomic dysfunction may predict poor prognosis in patients with multiple system atrophy 査読

Mari Tada, Osamu Onodera, Masayoshi Tada, Tetsutaro Ozawa, Yue-Shan Piao, Akiyoshi Kakita, Hitoshi Takahashi, Masatoyo Nishizawa

ARCHIVES OF NEUROLOGY 64 ( 2 ) 256 - 260 2007年2月

Early-onset ataxia with ocular motor apraxia and hypoalbuminemia is caused by mutations in a new HIT superfamily gene 査読

H Date, O Onodera, H Tanaka, K Iwabuchi, K Uekawa, S Igarashi, R Koike, T Hiroi, T Yuasa, Y Awaya, T Sakai, T Takahashi, H Nagatomo, Y Sekijima, Kawachi, I, Y Takiyama, M Nishizawa, N Fukuhara, K Saito, S Sugano, S Tsuji

NATURE GENETICS 29 ( 2 ) 184 - 188 2001年10月

Progressive atrophy of cerebellum and brainstem as a function of age and the size of the expanded CAG repeats in the MJD1 gene in Machado-Joseph disease 査読

O Onodera, J Idezuka, S Igarashi, Y Takiyama, K Endo, H Takano, M Oyake, H Tanaka, T Inuzuka, T Hayashi, T Yuasa, J Ito, T Miyatake, S Tsuji

ANNALS OF NEUROLOGY 43 ( 3 ) 288 - 296 1998年3月

Somatic mosaicism of expanded CAG repeats in brains of patients with dentatorubral-pallidoluysian atrophy: Cellular population-dependent dynamics of mitotic instability 査読

H Takano, O Onodera, H Takahashi, S Igarashi, M Yamada, M Oyake, T Ikeuci, R Koide, H Tanaka, K Iwabuchi, S Tsuji

AMERICAN JOURNAL OF HUMAN GENETICS 58 ( 6 ) 1212 - 1222 1996年6月

MOLECULAR-CLONING OF A FULL-LENGTH CDNA FOR DENTATORUBRAL-PALLIDOLUYSIAN ATROPHY AND REGIONAL EXPRESSIONS OF THE EXPANDED ALLELES IN THE CNS 査読

O ONODERA, M OYAKE, H TAKANO, T IKEUCHI, S IGARASHI, S TSUJI

AMERICAN JOURNAL OF HUMAN GENETICS 57 ( 5 ) 1050 - 1060 1995年11月

GENETIC ASSOCIATION OF THE VERY-LOW-DENSITY LIPOPROTEIN (VLDL) RECEPTOR GENE WITH SPORADIC ALZHEIMERS-DISEASE 査読

K OKUIZUMI, O ONODERA, Y NAMBA, K IKEDA, T YAMAMOTO, K SEKI, A UEKI, S NANKO, H TANAKA, H TAKAHASHI, K OYANAGI, H MIZUSAWA, KANAZAWA, I, S TSUJI

NATURE GENETICS 11 ( 2 ) 207 - 209 1995年10月

UNSTABLE EXPANSION OF CAG REPEAT IN HEREDITARY DENTATORUBRAL-PALLIDOLUYSIAN ATROPHY (DRPLA) 査読

R KOIDE, T IKEUCHI, O ONODERA, H TANAKA, S IGARASHI, K ENDO, H TAKAHASHI, R KONDO, A ISHIKAWA, T HAYASHI, M SAITO, A TOMODA, T MIIKE, H NAITO, F IKUTA, S TSUJI

NATURE GENETICS 6 ( 1 ) 9 - 13 1994年1月

Export‑biased, 3′UTR‑preserving TDP‑43 model links nuclear loss to cytoplasmic aggregation in ALS/FTLD

Genri Toyama, Shingo Koide, Takuma Yamagishi, Aya Washida, Ryutaro Hanyu, Osamu Onodera, Akihiro Sugai

2025年11月

Tongue shear wave elastography for bulbar dysfunction in amyotrophic lateral sclerosis

Kaori Yanagawa, Makiko Ike, Azusa Aoyama, Takeshi Yokoo, Shuji Terai, Takafumi Hayashi, Osamu Onodera

Clinical Neurophysiology 2025年11月

Association of Plasma Placental Growth Factor with White Matter Hyperintensities in Alzheimer’s Disease

Kazuya Igarashi, Tamao Tsukie, Kazuo Washiyama, Kiyoshi Onda, Yuki Miyagi, Shoya Inagawa, Soichiro Shimizu, Akinori Miyashita, Osamu Onodera, Takeshi Ikeuchi, Kensaku Kasuga

Biomolecules 2025年9月

Late-onset multiple system atrophy: Neuropathological features associated with slow disease progression. 国際誌

Misato Ozawa, Rie Saito, Takuya Konno, Yasuko Kuroha, Tetsuhiko Ikeda, Akio Yokoseki, Takashi Tani, Tomoe Sato, Jiro Idezuka, Reiji Koide, Shigeru Fujimoto, Osamu Onodera, Mari Tada, Akiyoshi Kakita

Brain pathology (Zurich, Switzerland) 35 ( 5 ) e70016 2025年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

Patients with late-onset (LO) multiple system atrophy (MSA), whose initial symptoms appear at age 75 years or older, are more common than previously assumed, but their clinicopathological characteristics remain unclear. We aimed to clarify the clinicopathological features of LO-MSA. Of 102 patients with autopsy-confirmed MSA, 5 were identified as having LO-MSA and 24 as having usual-age-onset MSA (UO-MSA) with a similar disease duration. On the basis of previous reports, we defined UO-MSA as the appearance of initial symptoms between the ages of 55 and 65 years. We compared the clinical pictures of the two groups and assessed their histopathological features using quantitative and semi-quantitative methods. The investigated features included the severity of degeneration in the striatonigral (StrN) and olivopontocerebellar (OPC) systems, the numbers of neurons in the brainstem autonomic and spinal intermediolateral nuclei, and the density of α-synuclein-immunopositive inclusions in the putamen, inferior olivary nucleus, and ventrolateral medulla (VLM). Most patients with both LO-MSA and UO-MSA exhibited the MSA-olivopontocerebellar atrophy (OPCA) subtype (3/5 and 18/24, respectively). The median disease duration for LO-MSA patients was 5.5 years, which was comparable to that for patients in our cohort who had developed symptoms below 75 years of age. Pathologically, degeneration of the StrN and OPC systems in LO-MSA was less severe than that observed in UO-MSA. Quantitative analysis revealed better preservation of neuron numbers in the brainstem autonomic nuclei in LO-MSA than in UO-MSA, with a significantly higher number of serotonergic neurons in the VLM (p = 0.013). The density of α-synuclein-positive inclusions in the putamen was significantly lower in LO-MSA than in UO-MSA (p < 0.001). Neuronal degeneration in LO-MSA may progress more slowly than in UO-MSA. Accordingly, the prognosis of LO-MSA may not necessarily be less favorable than that of MSA generally, especially with appropriate care.

DOI： 10.1111/bpa.70016

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Triheptanoin treatment in ataxia-telangiectasia: the significance of innovative clinical trials targeting mitochondrial dysfunction 国際誌

Osamu Onodera

eBioMedicine 119 105882 - 105882 2025年9月

Early-onset alopecia and variable age of cerebrovascular disease onset in a Japanese family with a heterozygous HTRA1 mutation. 国際誌

Manato Yasuda, Masahiro Mori, Atsuhiko Sugiyama, Tomoki Suichi, Toshio Fukutake, Masahiro Uemura, Osamu Onodera, Satoshi Kuwabara

Journal of the neurological sciences 475 123567 - 123567 2025年8月

Concurrent Alzheimer's disease pathologies in Lewy body diseases affect cognition and glucose metabolism in the posterior cingulate gyrus: A multimodal PET study. 国際誌

Kosei Nakamura, Kenji Tagai, Hitoshi Shinotoh, Shigeki Hirano, Soichiro Kitamura, Hironobu Endo, Keisuke Takahata, Yuhei Takado, Ming-Rong Zhang, Kazunori Kawamura, Osamu Onodera, Makoto Higuchi, Hitoshi Shimada

Journal of Alzheimer's disease : JAD 106 ( 3 ) 1074 - 1086 2025年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

BackgroundLewy body disease (LBD) is a neurodegenerative disease characterized by Lewy bodies, and it clinically presents dementia with Lewy bodies (DLB) and Parkinson's disease (PD). Alzheimer's disease (AD) pathologies frequently coexist with LBD, complicating the clinical manifestation.ObjectiveWe evaluated the impact of AD pathologies, including amyloid-β and tau depositions, on cognitive dysfunction and glucose metabolism in LBD using multiple positron emission tomography scans.MethodsOur study cohort consisted of 14 patients diagnosed with LBD, including five from the PD spectrum and nine from the DLB spectrum. In addition, 12 amyloid-negative cognitively healthy controls (HCs) and 13 amyloid-positive AD-spectrum patients were included. We subsequently explored the influence of amyloid and tau deposition on cognitive dysfunction and glucose metabolism among the LBD patients.ResultsIn the LBD group, 44.4% of the DLB patients were amyloid-positive, and all PD patients were amyloid-negative. While tau accumulation was lower than in AD and similar to HCs at the group level, tau accumulation in the AD signature region was correlated with cognitive dysfunction. Among the changes in glucose metabolism, the cingulate island sign (CIS) index was elevated compared to AD. However, as cognitive impairment progressed, the CIS index decreased, reflecting reduced metabolism in the posterior cingulate gyrus, which was closely associated with tau accumulation in the same region.ConclusionsOur findings indicate that AD pathologies, and particularly tau accumulation, significantly impact both cognitive dysfunction and glucose metabolism in LBD. This underscores the importance of addressing AD-related changes in the clinical management of LBD patients.

DOI： 10.1177/13872877251351220

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TDP-43 mutants with different aggregation properties exhibit distinct toxicity, axonal transport, and secretion for disease progression in a mouse ALS/FTLD model. 国際誌

Hideki Mori, Tokiharu Sato, Shintaro Tsuboguchi, Masahiko Takahashi, Yuka Nakamura, Kana Hoshina, Taisuke Kato, Masahiro Fujii, Osamu Onodera, Masaki Ueno

Neurobiology of disease 212 106988 - 106988 2025年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

TDP-43 accumulates and forms inclusions in neurons in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) and is assumed to cause neurodegenerative processes. The morphologies and cellular and areal distributions of accumulated TDP-43 inclusions are pathologically diverse among ALS/FTLD patients; however, whether and how different types of TDP-43 affect the process and severity of disease progression are not fully understood. Here, we compared the pathological events evoked by TDP-43 mutations, which have different aggregation properties, in cultured neurons and the cerebral cortex in mice. We selected TDP-43C173/175S and TDP-43G298S as aggregation-prone and nonprone mutants, respectively. Cytoplasmically expressed TDP-43C173/175S induced insoluble inclusions more robustly than TDP-43G298S did. In contrast, TDP-43G298S induced cell death more severely than TDP-43C173/175S. TDP-43G298S was further found to be efficiently transported in axons and led to axon degeneration, while this effect was not obvious in TDP-43C173/175S. Instead, TDP-43C173/175S was frequently trapped in the axon initial segments. Finally, TDP-43G298S was secreted in exosomes and transferred to oligodendrocyte-lineage cells in vitro more efficiently than TDP-43C173/175S to induce cell death. The transfer further evoked cytokine responses in microglial cells. These data revealed that different aggregation properties of TDP-43 cause distinct pathological events. These findings may explain the differences in the neurodegenerative progression and distribution observed among patients with ALS and FTLD.

DOI： 10.1016/j.nbd.2025.106988

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Specific Contribution of the Cerebellar Inferior Posterior Lobe to Motor Learning in Degenerative Cerebellar Ataxia. 国際誌

Kyota Bando, Takeru Honda, Kinya Ishikawa, Shinichi Shirai, Ichiro Yabe, Tomohiko Ishihara, Osamu Onodera, Yuichi Higashiyama, Fumiaki Tanaka, Yoshiyuki Kishimoto, Masahisa Katsuno, Takahiro Shimizu, Ritsuko Hanajima, Takumi Kanata, Yuji Takahashi, Hidehiro MizusawaMD

Cerebellum (London, England) 24 ( 5 ) 132 - 132 2025年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND AND OBJECTIVE: Degenerative cerebellar ataxia, a group of progressive neurodegenerative disorders, is characterised by cerebellar atrophy and impaired motor learning. Using CerebNet, a deep learning algorithm for cerebellar segmentation, this study investigated the relationship between cerebellar subregion volumes and motor learning ability. METHODS: We analysed data from 37 patients with degenerative cerebellar ataxia and 18 healthy controls. Using CerebNet, we segmented four cerebellar subregions: the anterior lobe, superior posterior lobe, inferior posterior lobe, and vermis. Regression analyses examined the associations between cerebellar volumes and motor learning performance (adaptation index [AI]) and ataxia severity (Scale for Assessment and Rating of Ataxia [SARA]). RESULTS: The inferior posterior lobe volume showed a significant positive association with AI in both single (B = 0.09; 95% CI: [0.03, 0.16]) and multiple linear regression analyses (B = 0.11; 95% CI: [0.008, 0.20]), an association that was particularly evident in the pure cerebellar ataxia subgroup. SARA scores correlated with anterior lobe, superior posterior lobe, and vermis volumes in single linear regression analyses, but these associations were not maintained in multiple linear regression analyses. This selective association suggests a specialised role for the inferior posterior lobe in motor learning processes. CONCLUSION: This study reveals the inferior posterior lobe's distinct role in motor learning in patients with degenerative cerebellar ataxia, advancing our understanding of cerebellar function and potentially informing targeted rehabilitation approaches. Our findings highlight the value of advanced imaging technologies in understanding structure-function relationships in cerebellar disorders.

DOI： 10.1007/s12311-025-01887-y

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[Hereditary Leukoencephalopathy: Overview to Definition, Diagnosis and Treatment].

Shin Koide, Shoichiro Ando, Osamu Onodera

Brain and nerve = Shinkei kenkyu no shinpo 77 ( 5 ) 561 - 568 2025年5月

記述言語：日本語掲載種別：研究論文（学術雑誌）

Hereditary leukoencephalopathies represent a heterogeneous group of inherited disorders characterized by abnormalities in the white matter of the brain. Recent advances in neuroimaging and genetic analyses have deepened our understanding of the underlying pathologies, leading to refined classification and diagnostic frameworks. Although many have no curative therapy, new treatments, such as hematopoietic stem cell transplantation, offer promising prospects for some of these diseases. Early and accurate diagnosis is critically important as it may improve management strategies and ultimately enhance patient outcomes.

DOI： 10.11477/mf.188160960770050561

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Long-Term Clinical Landscapes of Spinal Hypertrophic Pachymeningitis With Anti-Neutrophil Cytoplasmic Antibody–Associated Vasculitis 国際誌

Akihiro Nakajima, Mariko Hokari, Fumihiro Yanagimura, Etsuji Saji, Hiroshi Shimizu, Yasuko Toyoshima, Kaori Yanagawa, Musashi Arakawa, Akiko Yokoseki, Takahiro Wakasugi, Kouichirou Okamoto, Kei Watanabe, Keitaro Minato, Yutaka Otsu, Yukiko Nozawa, Daisuke Kobayashi, Kazuhiro Sanpei, Hirotoshi Kikuchi, Shunsei Hirohata, Kazuaki Awamori, Aya Nawata, Mitsunori Yamada, Hitoshi Takahashi, Masatoyo Nishizawa, Hironaka Igarashi, Noboru Sato, Akiyoshi Kakita, Osamu Onodera, Izumi Kawachi

Neurology 104 ( 8 ) e213420 2025年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Ovid Technologies (Wolters Kluwer Health)

BACKGROUND AND OBJECTIVES: Spinal hypertrophic pachymeningitis (HP) is an extremely rare disorder characterized by the thickening of the spinal dura mater, which harbors distinct repertoires of immune cells due to the unique partitioning of the arachnoid blood-CSF barrier. The objectives were to identify the pathogenesis and therapeutic strategies for spinal HP. METHODS: This retrospective cohort study analyzed the clinical and pathologic profiles of patients with idiopathic/immune-mediated HP including spinal HP. RESULTS: Among 61 patients with idiopathic/immune-mediated HP, all 6 Japanese patients with spinal HP, with a median observation period of 88.8 months, were myeloperoxidase (MPO)-anti-neutrophil cytoplasmic antibody (ANCA)-seropositive. The MPO-ANCA+ spinal HP cohort had the following characteristics: (1) a predominance of older women; (2) all patients were classified as having microscopic polyangiitis based on the 2022 American College of Rheumatology/European League Against Rheumatism criteria; (3) 83% of patients developed subacute/chronic myelopathy due to extramedullary spinal cord compression; (4) 50% of patients had lesion extension to the epidural compartment and vertebral column; (5) 50% of patients presented with chronic sinusitis, otitis media, or mastoiditis; (6) 33% of patients had involvement of the lower airways or kidneys; (7) a higher disease activity of the nervous system was noted based on the Birmingham Vasculitis Activity Score (BVAS), in contrast to MPO-ANCA+ cranial HP; (8) granulomatous inflammation with myofibroblasts, immune cells including granulocytes, and B-cell follicle-like structures were observed in the thickened dura mater; (9) immunotherapies (with or without surgical decompression) were effective in reducing the modified Rankin Scale score and reduced BVAS during the first active insults; (10) combined immunotherapies with glucocorticoids and cyclophosphamide/rituximab helped in reducing relapses in the long term; and (11) surgical decompression, including laminectomy and duraplasty, was necessary for compressive myelopathy. These data suggest that MPO-ANCA+ spinal HP shares common features with MPO-ANCA+ cranial HP (1, 2, 6, 8, 9, and 10), but also has unique clinical features (3, 4, 5, 7, and 11). DISCUSSION: Our findings highlight the significant pathogenic role of ANCA in spinal HP. MPO-ANCA+ spinal HP, as an organ-threatening disease, should be positioned as having unique characteristics, whether limited to the CNS or as part of a generalized form in ANCA-associated vasculitis.

DOI： 10.1212/wnl.0000000000213420

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Utility of Cerebrospinal Fluid Transferrin Receptor per Ferritin Ratio in Progressive Supranuclear Palsy 国際誌

Natsuki Akiyama, Masato Kanazawa, Kensaku Kasuga, Masahiro Hatakeyama, Takeshi Ikeuchi, Osamu Onodera

Movement Disorders Clinical Practice 12 ( 4 ) 446 - 452 2025年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Progressive supranuclear palsy (PSP) is a major atypical parkinsonism. Because diagnosis based on the cardinal clinical features is often difficult, misdiagnosis with Parkinson's disease (PD) and multiple system atrophy (MSA) is common in PSP patients. Iron metabolism genes are reportedly involved in tau-accumulating neuronal cell death and ferroptosis in PSP, which is more severe than PD and MSA. The validity of transferrin receptor (TfR) expression as a biomarker of ferroptosis was also demonstrated. OBJECTIVE: We investigated whether TfR and the TfR to ferritin ratio in the cerebrospinal fluid (CSF) is a diagnostic biomarker of PSP. METHODS: This study included 2 independent retrospective CSF cohorts comprising patients, respectively, from Niigata University and a multicenter memory clinic, consisting of patients with PSP, PD, and MSA. All patients were classified as clinically probable or higher based on the Society of Movement Disorders Criteria. TfR and ferritin levels in the CSF were measured using Luminex assay. RESULTS: The levels of TfR in patients with PSP were higher than those in patients with PD and MSA in cohort 1 (PSP: N = 16, PD: N = 13, MSA: N = 20). The TfR to ferritin ratio in patients with PSP was significantly higher than that in patients with MSA. Subsequently, we validated these results in cohort 2 (PSP: N = 23, MSA: N = 6). The TfR to ferritin ratio was significantly higher in patients with PSP than in those with MSA. CONCLUSIONS: The CSF TfR to transferrin ratio was elevated in patients with PSP. These results should be validated in a larger cohort of patients.

DOI： 10.1002/mdc3.14313

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Redefining the Pathogenic CAG Repeat Units Threshold in CACNA1A for Spinocerebellar Ataxia Type 6 国際誌

Yuya Hatano, Tomohiko Ishihara, Sachiko Hirokawa, Hidetoshi Date, Yuji Takahashi, Hidehiro Mizusawa, Osamu Onodera

Neurology Genetics 11 ( 2 ) e200245 2025年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND AND OBJECTIVES: Spinocerebellar ataxia type 6 (SCA6) is caused by expansion of CAG repeat units (RUs) in CACNA1A. While the pathologic threshold has been considered to be 20 or 21 RUs, the lower limit remains controversial. This study aimed to clarify the pathologic significance of RUs in SCA6, including the role of opposite alleles (OAs). METHODS: This was an observational study of patients with suspected spinocerebellar ataxia who underwent SCA6 genetic testing. We analyzed the relationship between CACNA1A RUs and age at onset (AAO). Family history positivity rates were examined for different RUs of the expanded allele (EA). Regression analyses were performed for AAO estimation based on the EA RUs. The influence of OAs on AAO was investigated, particularly in cases with 21-22 EA RUs. RESULTS: In total, 2,768 participants were enrolled. Family history positivity rates increased progressively above 19 RUs and plateaued at ≥23 RUs. Regression analysis of cases with ≥23 RUs showed that 96.20% of cases with ≥23 RUs, 90.67% of cases with 22 RUs, 91.15% of cases with 21 RUs, 61.54% of cases with 20 RUs, and 33.33% of cases with 19 RUs fell within the 95% prediction interval for AAO. However, no patients with ≤18 RUs were included. In the 21-22 RU group, OAs significantly influenced AAO, and ≥17 RUs had a significant effect. For ≥23 RUs, no significant OA effect was observed. Cases with 19-20 RUs showed a higher prevalence of OA with ≥19 RUs compared with cases with ≥23 RUs. DISCUSSION: Our findings suggest that clinical manifestation within a typical lifespan likely requires at least 19 RUs. The 19-20 RU range represents an intermediate zone where OA may influence disease likelihood. For 21-22 RUs, OA significantly affects AAO, indicating a complex interplay between EA and OA. ≥23 RUs seem sufficient to cause disease onset within a typical lifespan, regardless of OA. These results provide a new paradigm for SCA6 diagnosis and genetic counseling, emphasizing the need for cautious interpretation of the intermediate RU range and consideration of OA.

DOI： 10.1212/NXG.0000000000200245

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“Chocolate Chip Sign” on Susceptibility-Weighted Imaging 国際誌

Shoichiro Ando, Rie Saito, Sho Kitahara, Masahiro Uemura, Yuya Hatano, Masaki Watanabe, Taisuke Kato, Yosuke Ito, Atchayaram Nalini, Tomohiko Ishihara, Shigeo Murayama, Hironaka Igarashi, Akiyoshi Kakita, Osamu Onodera

Neurology Genetics 11 ( 2 ) e200237 2025年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Ovid Technologies (Wolters Kluwer Health)

BACKGROUND AND OBJECTIVES: HTRA1-related cerebral small vessel disease (HRSVD) is a rare hereditary form of cerebral small vessel disease (CSVD) caused by HTRA1 pathogenic variants. Diagnosing HRSVD without genetic testing is challenging because of the lack of distinctive imaging features and clinical symptoms, and even family history can be unclear in some cases with HRSVD. This study investigates whether susceptibility-weighted imaging (SWI) can identify useful diagnostic findings for HRSVD. METHODS: This retrospective study included 8 patients with HRSVD, 12 with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and 14 with sporadic CSVD (sCSVD). Two neurologists blinded to clinical data counted the number of hypointense dots around the midbrain on SWI. Receiver operating characteristic curve analysis evaluated the optimal threshold of the number that can distinguish HRSVD and CADASIL or sCSVD. In addition, histopathologic analysis including measurement of leptomeningeal vessel diameter and type III collagen deposition was performed on autopsied brains from 3 cases each of HRSVD, CADASIL, and sCSVD and control participants. RESULTS: Patients with HRSVD exhibited a significantly higher number of hypointense dots around the midbrain on SWI compared with CADASIL and sCSVD groups. A threshold of 5 or more dots, termed the "Chocolate Chip Sign," well distinguished HRSVD from CADASIL and sCSVD (area under the curve: 0.817, 95% confidence interval: 0.624-1.00). Three-dimensional SWI reconstruction and 7T MRI confirmed these dots as dilated extraparenchymal vessels. Histopathologic analysis revealed pronounced dilation of leptomeningeal veins with type III collagen accumulation specifically, in HRSVD brains. DISCUSSION: The Chocolate Chip Sign on SWI represents a novel and promising neuroimaging biomarker for HRSVD. This finding holds significant potential for facilitating early diagnosis, prompting timely genetic testing, and appropriate family screening for this rare genetic disorder.

DOI： 10.1212/nxg.0000000000200237

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Oxygen–glucose-deprived peripheral blood mononuclear cells act on hypoxic lesions after ischemia-reperfusion injury 国際誌

Takeshi Kanayama, Masahiro Hatakeyama, Natsuki Akiyama, Yutaka Otsu, Osamu Onodera, Takayoshi Shimohata, Masato Kanazawa

Experimental Neurology 385 115121 - 115121 2025年3月

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 BV

BACKGROUND: Despite advances in reperfusion therapies, ischemic stroke remains a major cause of long-term disability due to residual hypoxic lesions persisting after macrovascular reperfusion. These residual hypoxic lesions, caused by microvascular dysfunction, represent an important therapeutic target. We previously demonstrated that oxygen-glucose-deprived peripheral blood mononuclear cells (OGD-PBMCs) migrate to ischemic brain regions and promote functional recovery after stroke. This recovery occurs through mechanisms involving hypoxia-inducible factor-1α, exosomal miR-155-5p, and vascular endothelial growth factor (VEGF). However, it remains unclear whether OGD-PBMCs target hypoxic regions. METHODS: We evaluated cerebral blood flow using a laser speckle flow imaging system. Next, we utilized pimonidazole to investigate the presence of hypoxic lesions after ischemia-reperfusion injury in a rat suture occlusion model in immunohistochemical analyses. We also compared levels of a cell surface receptor in human PBMCs by flow cytometric analysis under normoxic and OGD conditions. RESULTS: We found persistent pimonidazole-positive hypoxic lesions at 10- and 28-days post-reperfusion despite restored gross cerebral perfusion. Treatment with the C-X-C motif chemokine receptor 4 (CXCR4) inhibitor AMD3100 before and after OGD-PBMCs administration reduced the number of OGD-PBMCs in the brain parenchyma compared to the control group (P = 0.018). Administered OGD-PBMCs localized within these hypoxic regions via the stromal cell-derived factor-1/CXCR4 chemotactic axis. OGD-PBMCs enhanced VEGF expression, specifically within hypoxic lesions, compared to the phosphate-buffered saline group (P < 0.01). Furthermore, OGD-PBMCs reduced the number of pimonidazole-positive hypoxic cells in the ischemic core on 28 days. These findings demonstrate that OGD-PBMCs selectively migrate to and modulate the microenvironment of hypoxic lesions following cerebral ischemia-reperfusion injury. CONCLUSION: Targeting these residual hypoxic regions may underline the therapeutic effects of OGD-PBMC treatment and represent a promising strategy for improving stroke recovery despite successful recanalization.

DOI： 10.1016/j.expneurol.2024.115121

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Frequency of FGF14 intronic GAA repeat expansion in patients with multiple system atrophy and undiagnosed ataxia in the Japanese population 国際誌

Toshiyuki Kakumoto, Kenta Orimo, Takashi Matsukawa, Jun Mitsui, Tomohiko Ishihara, Osamu Onodera, Yuta Suzuki, Shinichi Morishita, Ayaka Chikada, Kenta Orimo, Takashi Matsukawa, Tatsushi Toda, Jun Mitsui, Hiroyufki Ishiura, Koji Abe, Toru Yamashita, Hidehiro Mizusawa, Yuji Takahashi, Masahisa Katsuno, Kazuhiro Hara, Osamu Onodera, Tomohiko Ishihara, Masayoshi Tada, Satoshi Kuwabara, Atsuhiko Sugiyama, Yoshitaka Yamanaka, Ryosuke Takahashi, Yusuke Sakato, Tomoyuki Ishimoto, Nobukatsu Sawamoto, Ritsuko Hanajima, Yasuhiro Watanabe, Hiroshi Takigawa, Tadashi Adachi, Hiroshi Takashima, Keiko Higashi, Junichi Kira, Ichiro Yabe, Masaaki Matsushima, Katsuhisa Ogata, Kinya Ishikawa, Yoichiro Nishida, Taro Ishiguro, Kokoro Ozaki, Tetsuya Nagata, Shoji Tsuji, Tatsushi Toda, Shoji Tsuji

European Journal of Human Genetics 33 ( 3 ) 325 - 333 2025年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by autonomic nervous system dysfunction and cerebellar ataxia or parkinsonism. Recently, expanded GAA repeats (≥250 repeat units) in intron 1 of FGF14 have been shown to be responsible for spinocerebellar ataxia type 27B (SCA27B), a late-onset ataxia with an autosomal dominant inheritance. Patients with SCA27B may also exhibit autonomic nervous system dysfunction, potentially overlapping with the clinical presentations of MSA patients. In this study, to explore the possible involvement of expanded GAA repeats in MSA, we investigated the frequencies of expanded GAA repeats in FGF14 in 548 patients with MSA, 476 patients with undiagnosed ataxia, and 455 healthy individuals. To fully characterize the structures of the expanded GAA repeats, long-range PCR products suggesting the expansion of GAA repeats were further analyzed using a long-read sequencer. Of the 548 Japanese MSA patients, we identified one MSA patient (0.2%) carrying an expanded repeat with (GAA)≥250. Among the 476 individuals with undiagnosed ataxia, (GAA)≥250 was observed in six (1.3%); this frequency was higher than that in healthy individuals (0.2%). The clinical characteristics of the MSA patient with (GAA)≥250 were consistent with those of MSA, but not with SCA27B. Further research is warranted to explore the possibility of the potential association of expanded GAA repeats in FGF14 with MSA.

DOI： 10.1038/s41431-024-01743-3

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Early diagnosis of cryptococcal meningoencephalitis in HIV-negative patients: Integration of brain MRI and clinical findings. 国際誌

Kosei Nakamura, Masato Kanazawa, Yuka Koike, Takuya Konno, Osamu Onodera

eNeurologicalSci 38 100552 - 100552 2025年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

PURPOSE: Cryptococcal meningoencephalitis (CM) in human immunodeficiency virus (HIV)-negative patients are often diagnosed later than in HIV-infected patients, which increases mortality rates concerning the former. Consequently, early diagnosis and treatment are crucial for improving clinical prognosis in HIV-negative patients. This study investigated the utility of magnetic resonance imaging (MRI) in combination with clinical and laboratory findings for early diagnosis of CM in HIV-negative patients. METHODS: This retrospective cohort analysis included consecutive patients diagnosed with central nervous system (CNS) infections. Demographic profiles, laboratory findings, admission symptoms, and MRI findings were assessed. A comparative analysis between CM and other CNS infections was performed. RESULTS: Twelve HIV-negative patients were diagnosed with CM, while 38 exhibited other CNS infections (two fungal, 23 bacterial, 12 viral, one parasitic). Pseudocysts on MRI (p = 0.002), absence of fever (p = 0.001), headache (p = 0.005), and normal C-reactive protein (CRP) levels (p = 0.020) were specific findings in CM. By applying a cut-off value of one point in combination of pseudocysts, absence of fever, headache, and normal CRP levels in differentiating CM from other CNS infections, the sensitivity and specificity were calculated as 76.3 % and 91.7 %, respectively. CONCLUSION: Integrating pseudocysts, absence of fever, headache, and normal CRP levels predicts early CM diagnosis, potentially improving outcomes.

DOI： 10.1016/j.ensci.2025.100552

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Novel Aspects of Hereditary Spastic Paraplegia: A Clinicopathologic and Biochemical Study of a Patient With a Heterozygous GCH1 Variant. 国際誌

Shoko Hongo, Tetsuhiko Ikeda, Mari Tada, Rina Aida, Tetsuo Ozawa, Norikazu Hara, Akinori Miyashita, Takashi Nakajima, Osamu Onodera, Takeshi Ikeuchi, Hiroshi Ichinose, Akiyoshi Kakita

Neuropathology and applied neurobiology 51 ( 1 ) e70006 2025年2月

Clinical utility of CSF Aβ38 in Japanese research and clinical cohorts. 国際誌

Tamao Tsukie, Kensaku Kasuga, Masataka Kikuchi, Takanobu Ishiguro, Akinori Miyashita, Osamu Onodera, Takeshi Iwatsubo, Takeshi Ikeuchi

Alzheimer's & dementia (Amsterdam, Netherlands) 17 ( 2 ) e70125 2025年

記述言語：英語掲載種別：研究論文（学術雑誌）

INTRODUCTION: Previous studies have reported that cerebrospinal fluid (CSF) amyloid beta (Aβ42/Aβ38) performs comparably to Aβ42/Aβ40 in predicting amyloid positron emission tomography (PET) positivity in White cohorts. However, this finding has not been validated in diverse populations. Moreover, the utility of CSF Aβ38 in diagnosing various neurological diseases has not been fully understood. METHODS: We analyzed CSF Aβ38, Aβ40, Aβ42, phosphorylated tau181, and neurofilament light chain in Japanese research and clinical cohorts with Alzheimer's clinical syndrome (ACS) or non-ACS. RESULTS: CSF Aβ42/Aβ38 predicted amyloid PET positivity comparably to Aβ42/Aβ40. The levels of CSF Aβ38 were significantly lower in patients with progressive supranuclear palsy (PSP) and idiopathic normal pressure hydrocephalus (iNPH) than in those with other diseases. DISCUSSION: We validated the high diagnostic performance of CSF Aβ42/Aβ38 in Japanese patients with AD. CSF Aβ38 reduction may be a characteristic feature of PSP and iNPH. HIGHLIGHTS: The diagnostic value of cerebrospinal fluid (CSF) amyloid beta (Aβ)38 was examined in Japanese research and clinical cohorts.CSF Aβ42/Aβ38 and Aβ42/Aβ40 showed comparable performance to detect brain Aβ deposition.CSF Aβ42/Aβ38 and Aβ42/Aβ40 discordant group showed a characteristic profile.CSF Aβ38 and Aβ40 were prominently decreased in progressive supranuclear palsy and idiopathic normal pressure hydrocephalus.

DOI： 10.1002/dad2.70125

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The analysis of schizophrenia-like psychosis in dentatorubral-pallidoluysian atrophy. 国際誌

Ichiko Ikegami, Yuka Mitsuhashi Koike, Hideki Hayashi, Sachiko Hirokawa, Shoichiro Ando, Tomohiko Ishihara, Osamu Onodera

Frontiers in neurology 16 1564856 - 1564856 2025年

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Dentatorubral-pallidoluysian atrophy (DRPLA) is a progressive neurodegenerative disorder caused by expanded CAG repeats in the ATN1 gene, characterized by cerebellar ataxia, seizures, tremors, and myoclonus. Although approximately 10% of patients with DRPLA reportedly develop schizophrenia-like psychosis (SLP), the distinct association between the clinical course of DRPLA and SLP remains unclear. This study aimed to elucidate the clinical features of SLP in patients with DRPLA. METHODS: We reviewed 22 cases of pathologically or genetically confirmed DRPLA with SLP, including 21 from the literature and one from our institution. Patient data, including clinical features, treatment information, and disease course, were extracted and analyzed. RESULTS: The age of onset was categorized as juvenile (n = 6), early adult (n = 8), and late adult (n = 8). Initially, 10 patients presented with motor symptoms, with six exhibiting psychiatric symptoms and six with both motor and psychiatric symptoms simultaneously. Furthermore, three patients were initially diagnosed with schizophrenia, while four experienced progressive worsening of psychiatric symptoms. The number of CAG repeats ranged from 57 to 76 (mean, 66.0) in the 10 patients with a genetic diagnosis. Summarily, 12 patients received psychotropic medications, with nine showing improvement in delusions and hallucinations. CONCLUSION: SLP can manifest across all DRPLA forms (juvenile-, early adult-, and late adult-onset) and may precede or follow motor symptoms. The clinical course and efficacy of psychotropic medications in patients with DRPLA and SLP suggest a shared pathogenesis between DRPLA and schizophrenia.

DOI： 10.3389/fneur.2025.1564856

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A case of cerebral amyloid angiopathy with ipsilateral tau and contralateral amyloid PET uptake related to cadaveric dura mater implanted in childhood 国際誌

Yuki Hatakeyama, Atsushi Michael Kimura, Shintaro Tsuboguchi, Mikhail Ratanov, Kosei Nakamura, Masahiro Hatakeyama, Yukimi Nakamura, Masaki Watanabe, Yoshihiro Murakami, Yuko Saito, Shigeo Murayama, Kensaku Kasuga, Takeshi Ikeuchi, Hironaka Igarashi, Osamu Onodera, Hitoshi Shimada

European Journal of Nuclear Medicine and Molecular Imaging 52 ( 8 ) 2737 - 2739 2024年12月

Blood–brain barrier dysfunction in multiple system atrophy: A human postmortem study 国際誌

Ramil Gabdulkhaev, Hiroshi Shimizu, Masato Kanazawa, Yasuko Kuroha, Arika Hasegawa, Jiro Idezuka, Kazuki Tainaka, Osamu Onodera, Akiyoshi Kakita

Neuropathology 45 ( 3 ) 210 - 222 2024年12月

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

Multiple system atrophy (MSA) is a rare neurodegenerative disease characterized by an accumulation of phosphorylated α‐synuclein (p‐αsyn) in oligodendrocytes in the form of glial cytoplasmic inclusions (GCIs). In MSA, not only mature oligodendrocytes but also oligodendrocyte precursor cells (OPCs) are affected. The latter play an important role in remyelination by differentiating into mature oligodendrocytes, as well as maintaining the blood–brain barrier (BBB) by promoting the expression of tight junction proteins. We have hypothesized that in MSA, the BBB is impaired as a result of aberrant interactions between affected OPCs and the cerebral vasculature. To verify this hypothesis, we conducted a neuropathological examination of postmortem brains from MSA patients and control subjects, focusing on the primary motor area, one of the main regions affected in MSA. Using double immunofluorescence, we quantified the expression of tight junction protein claudin‐5 in capillary endothelial cells and found that it was significantly lower in MSA than in controls in both the gray matter and white matter. Furthermore, a significantly higher amount of fibrinogen was extravasated into the brain parenchyma in MSA patients than in controls. In addition, leakage of IgG was detected almost specifically in MSA brain parenchyma, as visualized in three dimensions by combining techniques of chemical tissue clearing and light sheet microscopy. Finally, we confirmed accumulation of p‐αsyn‐positive GCIs along the cerebral vasculature within OPCs. These results suggest that BBB dysfunction and associated fibrinogen extravasation are constant findings in MSA, presumably triggered by the deposition of p‐αsyn in perivascular OPCs.

DOI： 10.1111/neup.13021

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SMN2 gene copy number affects the incidence and prognosis of motor neuron diseases in Japan

Tomohiko Ishihara, Akihide Koyama, Naoki Atsuta, Mari Tada, Saori Toyoda, Kenta Kashiwagi, Sachiko Hirokawa, Yuya Hatano, Akio Yokoseki, Ryoichi Nakamura, Genki Tohnai, Yuishin Izumi, Ryuji Kaji, Mitsuya Morita, Asako Tamura, Osamu Kano, Masashi Aoki, Satoshi Kuwabara, Akiyoshi Kakita, Gen Sobue, Osamu Onodera

BMC Medical Genomics 17 ( 1 ) 2024年11月

L-arginine in patients with spinocerebellar ataxia type 6: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial 国際誌

Tomohiko Ishihara, Masayoshi Tada, Yoshitomi Kanemitsu, Yuji Takahashi, Kinya Ishikawa, Kensuke Ikenaka, Makito Hirano, Takanori Yokota, Eiko N. Minakawa, Katsuhisa Saito, Yoshitaka Nagai, Osamu Onodera

eClinicalMedicine 78 102952 - 102952 2024年11月

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 BV

BACKGROUND: Therapeutic advancements for the polyglutamine diseases, particularly spinocerebellar degeneration, are eagerly awaited. We evaluated the safety, tolerability, and therapeutic effects of L-arginine, which inhibits the conformational change and aggregation of polyglutamine proteins, in patients with spinocerebellar ataxia type 6 (SCA6). METHODS: A multicenter, randomized, double-blind, placebo-controlled phase 2 trial (clinical trial ID: AJA030-002, registration number: jRCT2031200135) was performed on 40 genetically confirmed SCA6 patients enrolled between September 1, 2020, and September 30, 2021. The main inclusion criteria were as follows: SCA6 diagnosed by genetic testing, 20 years of age or older, Scale for the Assessment and Rating of Ataxia (SARA) "walking" score of at least one point, and SARA "total" score of at least 10 points, and ability to walk 10 m or more with or without an assistive device. The investigational drug was administered orally at 0.50 g/kg/day (L-arginine group: L-arginine 0.38 g/kg/day; placebo group: L-arginine 0.0 g/kg/day) for 48 weeks. Subjects who consented to participate were assigned a subject identification code, and were allocated 1:1 to the L-arginine or the placebo group, according to a predetermined allocation chart. The primary efficacy endpoint was change in total Scale for the Assessment and Rating of Ataxia (SARA) score from baseline to 48 weeks. The secondary endpoints were 1) SARA walking + standing score, 2) each of the eight SARA scales at 0, 4, 8, 16, 24, 32, 40, and 48 weeks, and 3) TUGT, BDI-II, CGI, PGI-I, and SF-8. FINDINGS: Forty patients received the investigational drug, and 37 completed the study (L-arginine group: 18; placebo group: 19). The mean medication adherence rate was 97.2% in the l-arginine group. Regarding the primary endpoint, the difference between the L-arginine group and the placebo group was -1.52 (95% CI: -3.10 to 0.06, P = 0.0582). As the secondary endpoints, the change of SARA total score from baseline was greater in the L-arginine group than in the placebo group at all assessment time points, but the differences were not significant. Two serious (required hospitalization) adverse reactions occurred in the L-arginine group, including one case of pneumonia (severe, death) and one case of abnormal liver function (moderate, recovery). INTERPRETATION: L-arginine treatment resulted in an improvement tendency in SARA total score of SCA6 patients. Our results suggest that a phase 3 study of L-arginine for SCA6, with a 48-week observation period and change in total SARA score as the primary endpoint, may be feasible for further analyzing the therapeutic effect of L-arginine. However, careful consideration of statistical power and sample size is necessary. FUNDING: Japan Agency for Medical Research and Development and Health Labour Sciences Research Grant, Japan.

DOI： 10.1016/j.eclinm.2024.102952

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A case of isolated dystextia due to subcortical infarction: a novel condition of digital device era

Masahiro Hatakeyama, Takeshi Kanayama, Saori Tokunaga, Toshiya Kizaki, Shintaro Tsuboguchi, Masato Kanazawa, Osamu Onodera

BMC Neurology 24 ( 1 ) 2024年10月

本邦における抗LGI1脳炎の特徴自己免疫介在性脳炎・脳症の全国疫学調査

河内泉, 佐治越爾, 佐藤泰憲, 飯塚高浩, 木村暁夫, 佐久間啓, 中嶋秀人, 大石真莉子, 中島章博, 神田隆, 高橋幸利, 渡邊修, 鵜沢顕之, 桑原聡, 小野寺理

臨床神経学 64 ( Suppl. ) S252 - S252 2024年10月

本邦における抗NMDA受容体脳炎の特徴自己免疫介在性脳炎・脳症の全国疫学調査

佐治越爾, 佐藤泰憲, 飯塚高浩, 木村暁夫, 佐久間啓, 中嶋秀人, 大石真莉子, 中島章博, 神田隆, 高橋幸利, 渡邊修, 鵜沢顕之, 桑原聡, 小野寺理, 河内泉

臨床神経学 64 ( Suppl. ) S252 - S252 2024年10月

Qki5 safeguards spinal motor neuron function by defining the motor neuron-specific transcriptome via pre-mRNA processing. 国際誌

Yoshika Hayakawa-Yano, Takako Furukawa, Tsuyoshi Matsuo, Takahisa Ogasawara, Masahiro Nogami, Kazumasa Yokoyama, Masato Yugami, Munehisa Shinozaki, Chihiro Nakamoto, Kenji Sakimura, Akihide Koyama, Kazuhiro Ogi, Osamu Onodera, Hirohide Takebayashi, Hideyuki Okano, Masato Yano

Proceedings of the National Academy of Sciences of the United States of America 121 ( 37 ) e2401531121 2024年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

Many RNA-binding proteins (RBPs) are linked to the dysregulation of RNA metabolism in motor neuron diseases (MNDs). However, the molecular mechanisms underlying MN vulnerability have yet to be elucidated. Here, we found that such an RBP, Quaking5 (Qki5), contributes to formation of the MN-specific transcriptome profile, termed "MN-ness," through the posttranscriptional network and maintenance of the mature MNs. Immunohistochemical analysis and single-cell RNA sequencing (scRNA-seq) revealed that Qki5 is predominantly expressed in MNs, but not in other neuronal populations of the spinal cord. Furthermore, comprehensive RNA sequencing (RNA-seq) analyses revealed that Qki5-dependent RNA regulation plays a pivotal role in generating the MN-specific transcriptome through pre-messenger ribonucleic acid (mRNA) splicing for the synapse-related molecules and c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) signaling pathways. Indeed, MN-specific ablation of the Qki5 caused neurodegeneration in postnatal mice and loss of Qki5 function resulted in the aberrant activation of stress-responsive JNK/SAPK pathway both in vitro and in vivo. These data suggested that Qki5 plays a crucial biological role in RNA regulation and safeguarding of MNs and might be associated with pathogenesis of MNDs.

DOI： 10.1073/pnas.2401531121

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Lessons from the ATTeST trial in ataxia telangiectasia. 国際誌

Yuka Koike, Osamu Onodera

The Lancet. Neurology 23 ( 9 ) 846 - 847 2024年9月

Indications for a brain biopsy in neurological diseases of unknown etiology: The role of magnetic resonance imaging findings and liquid biopsy in yielding definitive pathological diagnoses. 国際誌

Toshiya Kizaki, Masato Kanazawa, Takanobu Ishiguro, Manabu Natsumeda, Mari Tada, Hiroshi Shimizu, Kouichirou Okamoto, Makoto Oishi, Akiyoshi Kakita, Yukihiko Fujii, Osamu Onodera

Journal of the neurological sciences 463 123150 - 123150 2024年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

Brain biopsies are often considered for patients who cannot be diagnosed with various laboratory test results. However, physicians tend to be hesitant regarding their application in possibly non-neoplastic brain diseases, due to the invasiveness and risks. The aim was to determine the indications for brain biopsies in cases of neurological diseases of unknown etiology. We retrospectively evaluated diagnostic accuracy, laboratory findings (including a liquid biopsy for malignant lymphoma), magnetic resonance imaging (MRI) characteristics and the post-treatment outcomes of patients undergoing brain biopsies for neurological diseases of unknown etiology. The data of patients who had undergone a brain biopsy during their admission to Niigata University Hospital, between 2011 and 2024, were reviewed. Moreover, the laboratory data and MRI findings between patients with definitive and nonspecific biopsy diagnoses were compared. Twenty-six patients underwent a brain biopsy, and a definitive diagnosis was obtained in 14 patients (53.8%). Even in cases where a nonspecific diagnosis was made, biopsy findings helped rule out malignancy and guide clinical diagnosis and treatment decisions. The liquid biopsy for malignant lymphoma was performed in eight patients, with one yielding a positive result, consistent with primary central nervous system lymphoma. The sensitivity and specificity of liquid biopsy were 0.5 and 1, respectively. Diffusely contrasted cortical lesions and the presence of mass effects on MRI, were significantly associated with a definitive diagnosis, compared to a nonspecific diagnosis. In conclusion, brain MRI and liquid biopsies can assist in determining the appropriate indications for brain biopsies in neurological diseases of unknown etiology.

DOI： 10.1016/j.jns.2024.123150

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A patient with neuronal intranuclear inclusion disease developed encephalitis‐like symptoms after cerebral angiography

Shin Koide, Shintaro Tsuboguchi, Shingo Koide, Itaru Ninomiya, Taiki Saito, Takanobu Ishiguro, Etsuji Saji, Yo Higuchi, Takeshi Ikeuchi, Makoto Oishi, Masato Kanazawa, Osamu Onodera

Neurology and Clinical Neuroscience 2024年6月

掲載種別：研究論文（学術雑誌）出版者・発行元：Wiley

Abstract

Patients with neuronal intranuclear inclusion disease (NIID) can present with encephalitis‐like symptoms such as recurrent paroxysmal fever and unconsciousness. To date, no specific triggers for these symptoms have been reported. In our case, an 78‐year‐old woman became unconscious and developed fever after cerebral angiography. The patient had experienced four episodes of unconsciousness and fever in the past 7 years. Postangiography, she immediately became unconscious and developed fever. No vascular abnormalities were found and magnetic resonance imaging of the brain revealed expanding white matter lesions and hyperintense lesions along the corticomedullary junction. Genetic analysis revealed an abnormal GGC repeat expansion in NOTCH2NLC. Thus, we diagnosed the patient with NIID. We suggest that cerebral angiography is a possible trigger for encephalitis‐like symptoms in NIID.

DOI： 10.1111/ncn3.12839

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Cerebellar compensation: a case of aphasia due to cerebellar hemorrhage

Yukiko Kinoshita, Masahiro Hatakeyama, Mika Otsuki, Takanobu Ishiguro, Etsuji Saji, Masato Kanazawa, Osamu Onodera

Journal of Neurology 2024年6月

UCP2 polymorphisms, daily step count, and number of teeth associated with all-cause mortality risk in Sado City: A hospital-based cohort study

Han Lyu, Noriko Sugita, Shigeki Komatsu, Minako Wakasugi, Akio Yokoseki, Akihiro Yoshihara, Tetsuo Kobayashi, Kenji Sato, Hiroyuki Kawashima, Osamu Onodera, Ichiei Narita, Koichi Tabeta

Heliyon 10 ( 12 ) e32512 - e32512 2024年6月

造影効果を伴う多発脳病変を呈し,悪性腫瘍との鑑別を要したウイルス性髄膜脳炎の73歳女性の一例

柏木健太, 大津裕, 岸諒太, 福本淳貴, 石黒敬信, 佐治越爾, 金澤雅人, 小野寺理

臨床神経学 64 ( 6 ) 438 - 438 2024年6月

From bench to bedside: US-Japan Collaborative Workshop on the NVU

Cesario Borlongan, Elga Esposito, Laarni Grace Corales, Yorito Hattori, Yu Hayashi, Masafumi Ihara, Jeffrey J. Iliff, Kassandra Kisler, Shinobu Kitazume, Schuichi Koizumi, Jialing Liu, Takakuni Maki, Osamu Onodera, Satoshi Saito, Kazunobu Sawamoto, Kazuhiro Sohya, Akihiko Taguchi, Shinichi Takahashi, Kenji Tanaka, Toshiaki Taoka, Hiroaki Wake, Michisuke Yuzaki

The Journal of Physiological Sciences 74 ( S1 ) 2024年5月

掲載種別：研究論文（学術雑誌）出版者・発行元：Springer Science and Business Media LLC

Abstract

The joint workshop between U.S. and Japanese researchers, supported by The U.S.–Japan Brain Research Cooperative Program, convened in January 2023 at Keio University Mita campus in Tokyo, Japan. The workshop had a threefold objective. Firstly, it aimed to facilitate robust exchanges between U.S. and Japanese researchers engaged in Neurovascular Unit (NVU) research, enhancing the global network of scholars in the field. Secondly, it aimed to encourage the initiation of collaborative research projects, fostering interdisciplinary efforts and synergistic advancements in understanding the brain vascular physiology and central nervous system. Lastly, the workshop emphasized the nurturing of young researchers, recognizing their pivotal role in shaping the future of NVU research. Throughout the workshop, participants discussed fundamental aspects of the NVU, exploring its complex connections and vital functions. By sharing their expertise and insights, the workshop attendees sought to uncover novel approaches to mitigate the burden of neurological diseases for individuals worldwide. This report provides a summary of the presentations and discussions held during the workshop, showcasing the collective efforts and progress made by the participants.

DOI： 10.1186/s12576-024-00917-4

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その他リンク： https://link.springer.com/article/10.1186/s12576-024-00917-4/fulltext.html

Distal CIDPと鑑別を要したが、M蛋白やVEGFの再検が診断に有用であったPOEMS症候群の一例

鈴木大介, 鈴木佑弥, 菊池謙次, 鈴木義広, 小出伸, 安藤昭一朗, 石黒敬信, 金澤雅人, 小野寺理, 諏訪部達也, 瀧澤淳

臨床神経学 64 ( 5 ) 365 - 365 2024年5月

Stage-dependent immunity orchestrates AQP4 antibody-guided NMOSD pathology: a role for netting neutrophils with resident memory T cells in situ

Akihiro Nakajima, Fumihiro Yanagimura, Etsuji Saji, Hiroshi Shimizu, Yasuko Toyoshima, Kaori Yanagawa, Musashi Arakawa, Mariko Hokari, Akiko Yokoseki, Takahiro Wakasugi, Kouichirou Okamoto, Hirohide Takebayashi, Chihiro Fujii, Kyoko Itoh, Yo-ichi Takei, Shinji Ohara, Mitsunori Yamada, Hitoshi Takahashi, Masatoyo Nishizawa, Hironaka Igarashi, Akiyoshi Kakita, Osamu Onodera, Izumi Kawachi

Acta Neuropathologica 147 ( 1 ) 2024年4月

Acute respiratory failure caused by brainstem demyelinating lesions in an older patient with an atypical relapsing autoimmune disorder

Shoko Hongo, Hiroshi Shimizu, Etsuji Saji, Akihiro Nakajima, Kouichirou Okamoto, Izumi Kawachi, Osamu Onodera, Akiyoshi Kakita

Neuropathology 2024年4月

掲載種別：研究論文（学術雑誌）出版者・発行元：Wiley

An 84‐year‐old man presented with somnolence, dysphagia, and right hemiplegia, all occurring within a month, approximately one year after initial admission due to subacute, transient cognitive decline suggestive of acute disseminated encephalomyelitis involving the cerebral white matter. Serial magnetic resonance imaging (MRI) studies over that period revealed three high‐intensity signal lesions on fluid‐attenuated inversion recovery images, appearing in chronological order in the left upper and left lower medulla oblongata and left pontine base. Despite some clinical improvement following methylprednisolone pulse therapy, the patient died of respiratory failure. Autopsy revealed four fresh, well‐defined lesions in the brainstem, three of which corresponded to the lesions detected radiologically. The remaining lesion was located in the dorsal medulla oblongata and involved the right solitary nucleus. This might have appeared at a later disease stage, eventually causing respiratory failure. Histologically, all four lesions showed loss of myelin, preservation of axons, and infiltration of lymphocytes, predominantly CD8‐positive T cells, consistent with the histological features of autoimmune demyelinating diseases, particularly the confluent demyelination observed in the early and acute phases of multiple sclerosis (MS). In the cerebral white matter, autoimmune demyelination appeared superimposed on ischemic changes, consistent with the cerebrospinal fluid (CSF) and MRI findings on initial admission. No anti‐AQP4 or MOG antibodies or those potentially causing autoimmune encephalitis/demyelination were detected in either the serum or CSF. Despite several similarities to MS, such as the relapsing–remitting disease course and lesion histology, the entire clinicopathological picture in the present patient, especially the advanced age at onset and development of brainstem lesions in close proximity within a short time frame, did not fit those of MS or other autoimmune diseases that are currently established. The present results suggest that exceptionally older individuals can be affected by an as yet unknown inflammatory demyelinating disease of the CNS.

DOI： 10.1111/neup.12976

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Dysregulation of stress granule dynamics by DCTN1 deficiency exacerbates TDP-43 pathology in Drosophila models of ALS/FTD

Tetsuhiro Ueda, Toshihide Takeuchi, Nobuhiro Fujikake, Mari Suzuki, Eiko N. Minakawa, Morio Ueyama, Yuzo Fujino, Nobuyuki Kimura, Seiichi Nagano, Akio Yokoseki, Osamu Onodera, Hideki Mochizuki, Toshiki Mizuno, Keiji Wada, Yoshitaka Nagai

Acta Neuropathologica Communications 12 ( 1 ) 2024年2月

掲載種別：研究論文（学術雑誌）出版者・発行元：Springer Science and Business Media LLC

Abstract

The abnormal aggregation of TDP-43 into cytoplasmic inclusions in affected neurons is a major pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although TDP-43 is aberrantly accumulated in the neurons of most patients with sporadic ALS/FTD and other TDP-43 proteinopathies, how TDP-43 forms cytoplasmic aggregates remains unknown. In this study, we show that a deficiency in DCTN1, a subunit of the microtubule-associated motor protein complex dynactin, perturbs the dynamics of stress granules and drives the formation of TDP-43 cytoplasmic aggregation in cultured cells, leading to the exacerbation of TDP-43 pathology and neurodegeneration in vivo. We demonstrated using a Drosophila model of ALS/FTD that genetic knockdown of DCTN1 accelerates the formation of ubiquitin-positive cytoplasmic inclusions of TDP-43. Knockdown of components of other microtubule-associated motor protein complexes, including dynein and kinesin, also increased the formation of TDP-43 inclusions, indicating that intracellular transport along microtubules plays a key role in TDP-43 pathology. Notably, DCTN1 knockdown delayed the disassembly of stress granules in stressed cells, leading to an increase in the formation of pathological cytoplasmic inclusions of TDP-43. Our results indicate that a deficiency in DCTN1, as well as disruption of intracellular transport along microtubules, is a modifier that drives the formation of TDP-43 pathology through the dysregulation of stress granule dynamics.

DOI： 10.1186/s40478-024-01729-8

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その他リンク： https://link.springer.com/article/10.1186/s40478-024-01729-8/fulltext.html

Validation study of the Japanese version of the King's Parkinson's Disease Pain Scale and the King's Parkinson's Disease Pain Questionnaire. 国際誌

Kanako Kurihara, Shinsuke Fujioka, Yasuaki Mizutani, Hirohisa Watanabe, Kazuhiro Iwaoka, Tetsuya Maeda, Morinobu Seki, Toshiki Tezuka, Jin Nakahara, Takuya Konno, Takanobu Ishiguro, Osamu Onodera, Yuri Asano, Kazushi Takahashi, Alexandra Rizos, K Ray Chaudhuri, Yoshio Tsuboi

Parkinsonism & related disorders 120 106012 - 106012 2024年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

INTRODUCTION: The King's Parkinson's Disease Pain Scale (KPPS)/King's Parkinson's Disease Pain Questionnaire (KPPQ) was developed as a tool to quantitatively assess pain in patients with Parkinson's disease (PwPD). Here, we conducted a Japanese multicenter validation study to verify the reliability of KPPS/KPPQ in Japanese PwPD. METHODS: PwPD, ≥20 years, with unexplained pain were included; those with a definitive primary cause of pain other than PD were excluded. A total of 151 patients who fulfilled the criteria were analyzed, and test-retest reliability was investigated in 25 individuals. RESULTS: The 151 patients included 101 women (66.9 %); mean age 68.3 ± 9.9 years, mean disease duration 9.2 ± 5.2 years. The most frequent pain type in the KPPS classification was musculoskeletal pain (82.8 %). There was a positive correlation between KPPS total score and the Non-Motor Symptoms Scale (NMSS) total score, NMSS item 27, the Parkinson's disease sleep scale-version 2 (PDSS-2) total score, PDSS-2 item 10, the Parkinson's Disease Questionnaire-8 (PDQ-8) summary index and PDQ-8 item 7. Cronbach's alpha of KPPS was 0.626 (0.562-0.658) and the intraclass correlation coefficient of test-retest reliability was 0.740. Cronbach's alpha of KPPQ was 0.660 (0.617-0.705) and a test-retest reliability of kappa coefficient was 0.593 (0.0-1.0). CONCLUSIONS: KPPS correlated well with other scales for assessing pain. KPPS correlated well with patients' quality of life, non-motor symptoms, and sleep disturbances. The reproducibility of KPPS/KPPQ makes it suitable for continuous evaluation of the same patient. On the other hand, the internal consistency of KPPS/KPPQ is rather low.

DOI： 10.1016/j.parkreldis.2024.106012

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Corrigendum: Regeneration of the cerebral cortex by direct chemical reprogramming of macrophages into neuronal cells in acute ischemic stroke. 国際誌

Itaru Ninomiya, Akihide Koyama, Yutaka Otsu, Osamu Onodera, Masato Kanazawa

Frontiers in cellular neuroscience 18 1372045 - 1372045 2024年

The Japan MSA registry: A multicenter cohort study of multiple system atrophy

Ayaka Chikada, Kenta Orimo, Jun Mitsui, Takashi Matsukawa, Hiroyuki Ishiura, Tatsushi Toda, Hidehiro Mizusawa, Yuji Takahashi, Masahisa Katsuno, Kazuhiro Hara, Osamu Onodera, Tomohiko Ishihara, Masayoshi Tada, Satoshi Kuwabara, Atsuhiko Sugiyama, Yoshitaka Yamanaka, Ryosuke Takahashi, Nobukatsu Sawamoto, Yusuke Sakato, Tomoyuki Ishimoto, Ritsuko Hanajima, Yasuhiro Watanabe, Hiroshi Takigawa, Tadashi Adachi, Koji Abe, Toru Yamashita, Hiroshi Takashima, Keiko Higashi, Junichi Kira, Ichiro Yabe, Masaaki Matsushima, Katsuhisa Ogata, Kinya Ishikawa, Yoichiro Nishida, Taro Ishiguro, Kokoro Ozaki, Tetsuya Nagata, Shoji Tsuji

Neurology and Clinical Neuroscience 2024年

Reliability study for the Japanese version of the Columbia Muscle Cramp Scale in amyotrophic lateral sclerosis

Masahiro Sawada, Takehisa Hirayama, Masaru Yanagihashi, Koji Fukushima, Yuishin Izumi, Tameto Naoi, Mitsuya Morita, Hitoshi Warita, Masashi Aoki, Yohei Iguchi, Masahisa Katsuno, Nobuhiro Ogawa, Makoto Urusitani, Tomohiko Ishihara, Osamu Onodera, Yoshitaka Murakami, Hiroshi Mitsumoto, Osamu Kano

Neurology and Clinical Neuroscience 2024年

Case report: Progressive multifocal leukoencephalopathy co-occurring with neurosarcoidosis: early brain biopsy and appropriate therapy for PML resulted in a favorable prognosis. 国際誌

Qiannan Wang, Shintaro Tsuboguchi, Kouichirou Okamoto, Mari Tada, Akiyoshi Kakita, Kazuo Nakamichi, Makoto Oishi, Masato Kanazawa, Osamu Onodera

Frontiers in immunology 15 1447992 - 1447992 2024年

記述言語：英語掲載種別：研究論文（学術雑誌）

Progressive multifocal leukoencephalopathy (PML) is a rare central nervous system disease caused by JC virus (JCV) infection. Human immunodeficiency virus (HIV) infection is the greatest risk factor for PML. Other immunological diseases, including systemic sarcoidosis, have also been reported as risk factors for PML. Herein, we report a case of PML co-occurring with neurosarcoidosis. Early diagnosis using brain biopsy and appropriate therapeutic interventions achieved favorable outcomes. PML in patients with active intracranial neurosarcoidosis is extremely rare. We believe that it is important to perform brain biopsy at an early stage to allow diagnosis, even for central nervous system involvement with a progressive parenchymal lesion in patients with sarcoidosis, if PML is possible.

DOI： 10.3389/fimmu.2024.1447992

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Two cases of cerebral hemorrhage with ipsilateral hemichorea-hemiballism

Shinya Oginezawa, Shoichiro Ando, Yukiko Kinoshita, Shoko Aburatani, Ryota Kishi, Yutaka Otsu, Takanobu Ishiguro, Etsuji Saji, Masato Kanazawa, Osamu Onodera

Japanese Journal of Stroke 2024年

Japanese longitudinal biomarker study in progressive supranuclear palsy and corticobasal degeneration: Clinical features of the first registered patients and short-term follow-up analysis

Hiroshi Takigawa, Ritsuko Hanajima, Ikuko Aiba, Takayoshi Shimohata, Takahiko Tokuda, Mitsuya Morita, Osamu Onodera, Shigeo Murayama, Kazuko Hasegawa, Aya M. Tokumaru, Hisanori Kowa, Masato Kanazawa, Tameto Naoi, Kenji Nakashima, Takeshi Ikeuchi

Clinical Parkinsonism & Related Disorders 2024年

Clinicopathologic features of two unrelated autopsied patients with Charcot-Marie-Tooth disease carrying MFN2 gene mutation. 国際誌

Hideki Hayashi, Rie Saito, Hidetomo Tanaka, Norikazu Hara, Shin Koide, Yosuke Yonemochi, Tetsuo Ozawa, Mariko Hokari, Yasuko Toyoshima, Akinori Miyashita, Osamu Onodera, Kouichirou Okamoto, Takeshi Ikeuchi, Takashi Nakajima, Akiyoshi Kakita

Acta neuropathologica communications 11 ( 1 ) 207 - 207 2023年12月

Missense Variants in COL4A1/2 Are Associated with Cerebral Aneurysms: A Case Report and Literature Review

Masahiro Uemura, Natsuki Tanaka, Shoichiro Ando, Takehiko Yanagihara, Osamu Onodera

Neurology International 2023年12月

Neuroprotective effects of oral metformin before stroke on cerebral small-vessel disease. 国際誌

Natsuki Akiyama, Takayuki Yamashiro, Itaru Ninomiya, Masahiro Uemura, Yorito Hattori, Masafumi Ihara, Osamu Onodera, Masato Kanazawa

Journal of the neurological sciences 456 122812 - 122812 2023年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Metformin (MET) treatment prior to stroke might have neuroprotective effects other than hypoglycemic effects. This study evaluated whether MET treatment prior to stroke is associated with neurological severity and functional outcome in patients with stroke who were not indicated for endovascular treatment and whether the effects of MET differ for each ischemic stroke subtype. METHODS: We investigated 160 type 2 diabetes mellitus patients with ischemic stroke without endovascular treatment who were taking some oral antidiabetic agents prior to stroke in two tertiary hospitals. Lower neurological severity was defined as a National Institutes of Health Stroke Scale score of 3 or lower on admission, and favorable functional outcome was defined as a modified Rankin Scale score = 0-2 at discharge. We analyzed the effects of MET on the neurological severity and functional outcome in each ischemic stroke subtype on logistic regression analysis with adjustments for multiple confounding factors. RESULTS: MET treatment prior to stroke was associated with lower stroke severity and favorable functional outcome. In the stroke subtypes, MET use affected both neurological severity (P = 0.037) and functional outcome (P = 0.041) in only patients with small-vessel disease (SVD). CONCLUSIONS: MET may be useful to improve the outcome of patients with SVD.

DOI： 10.1016/j.jns.2023.122812

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Marked laterality of olivopontocerebellar pathology in an autopsied patient with MSA: Implications for degeneration and α-synuclein propagation. 国際誌

Misato Ozawa, Rie Saito, Takuya Konno, Reiji Koide, Shigeru Fujimoto, Osamu Onodera, Akiyoshi Kakita

Journal of neurology, neurosurgery, and psychiatry 2023年11月

小脳出血で失語症を呈した一例

木下悠紀子, 畠山公大, 大槻美佳, 石黒敬信, 佐治越爾, 金澤雅人, 小野寺理

臨床神経学 63 ( 11 ) 772 - 772 2023年11月

A case report of reversible cerebral vasoconstriction syndrome with thunderclap headache significantly exacerbated in the supine position and alleviated in the standing position. 国際誌

Genri Toyama, Shintaro Tsuboguchi, Kazuya Igarashi, Etsuji Saji, Takuya Konno, Osamu Onodera

BMC neurology 23 ( 1 ) 348 - 348 2023年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by sudden onset thunderclap headache and multiple segmental reversible cerebral vasoconstrictions that improve within 3 months. The postpartum period is a well-known precipitating factor for the onset of RCVS. Cerebral venous thrombosis (CVT) causes thunderclap headaches in the postpartum period. While headache in CVT is sometimes exacerbated in the supine position, the severity of the headache in RCVS is usually independent of body position. In this study, we report a case of RCVS with thunderclap headache exacerbated in the supine position, and headache attacks that resolved quickly in the standing position during the postpartum period. CASE PRESENTATION: A 33-year-old woman presented with a sudden increase in blood pressure and thunderclap headache on the fifth postpartum day (day 1: the first sick day). The headache was severe and pulsatile, with onset in the supine position in bed, and peaked at approximately 10 s. It was accompanied by nausea and chills but there were no scintillating scotomas or ophthalmic symptoms. The headache resolved in the standing or sitting position but was exacerbated and became unbearable within a few seconds when the patient was in the supine position. Therefore, she was unable to lie supine at night. Computed tomography angiography (CTA) of the head on day 2 and magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) on day 3 showed no abnormalities. However, considering the possibility of RCVS, verapamil was initiated on day 3. The headache resolved the following day. MRA of the head on day 10 revealed diffuse and segmental stenoses in the bilateral middle and posterior cerebral arteries and basilar artery. Therefore, the patient was diagnosed with RCVS. The headache gradually resolved and disappeared completely on day 42. Cerebral vasoconstriction was also improved on MRA on day 43. CONCLUSIONS: This postpartum RCVS case was notable for the exacerbation of headaches in the supine position. For the diagnosis of thunderclap headache in the postpartum period, RCVS should be considered in addition to CVT when the patient presents with a headache that is exacerbated in the supine position.

DOI： 10.1186/s12883-023-03381-6

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アルツハイマー連続体における脳脊髄液αシヌクレインの臨床的有用性の検討

五十嵐一也, 春日健作, 月江珠緒, 菊地正隆, 宮下哲典, 小野寺理, 岩坪威, 池内健, Japanese Alzheimer's Disease Neuroimaging Initiative

Dementia Japan 37 ( 4 ) 687 - 687 2023年10月

若年性認知症の初診時臨床的特徴と脳脊髄液バイオマーカーの比較

大滝悠莉, 春日健作, 月江珠緒, 宮下哲典, 小野寺理, 池内健

Dementia Japan 37 ( 4 ) 684 - 684 2023年10月

脳アミロイドアンギオパチー関連炎症における脳脊髄液バイオマーカー

徳武孝允, 春日健作, 月江珠緒, 石黒敬信, 五十嵐一也, 小野寺理, 池内健

Dementia Japan 37 ( 4 ) 664 - 664 2023年10月

進行性核上性麻痺の脳脊髄液バイオマーカーによるAT(N)分類と臨床像

石黒敬信, 春日健作, 渡邉緑, 木下悠紀子, 月江珠緒, 小野寺理, 池内健

Dementia Japan 37 ( 4 ) 662 - 662 2023年10月

脳脊髄液アミロイドβ(Aβ)38の臨床的意義の検討

月江珠緒, 春日健作, 菊地正隆, 五十嵐一也, 大滝悠莉, 石黒敬信, 宮下哲典, 小野寺理, 岩坪威, 池内健, J-ADNI

Dementia Japan 37 ( 4 ) 658 - 658 2023年10月

リアルワールドにおける血漿バイオマーカーの有用性の検討

春日健作, 月江珠緒, 五十嵐一也, 石黒敬信, 宮下哲典, 小野寺理, 池内健

Dementia Japan 37 ( 4 ) 658 - 658 2023年10月

TDP-43は運動回路の変性を誘導するために異なって伝播する(TDP-43 differentially propagates to induce degeneration in the motor circuit)

坪口晋太朗, 中村由香, 石原智彦, 加藤泰介, 佐藤時春, 小山哲秀, 森秀樹, 小池佑佳, 小野寺理, 上野将紀

Dementia Japan 37 ( 4 ) 680 - 680 2023年10月

The Multifaceted Regulation of TDP-43 Condensates at the Intersection of Physiology and Pathology: Implications for Neurodegenerative Diseases

Akihiro Sugai, Takuma Yamagishi, Shingo Koide, Osamu Onodera

Phase Separation in Living Cells 253 - 270 2023年9月

発作性の神経症状を繰り返し、多発する微小出血像を認めた硬膜移植歴を有する39歳男性例

畠山祐樹, 坪口晋太朗, 石黒敬信, 佐治越爾, 畠山公大, 島田斉, 金澤雅人, 小野寺理

臨床神経学 63 ( 9 ) 603 - 603 2023年9月

SCA6の浸透性に関する研究(Study of penetrance of SCA6)

Hatano Yuya, Ishihara Tomohiko, Hirokawa Sachiko, Onodera Osamu

臨床神経学 63 ( Suppl. ) S335 - S335 2023年9月

脳梗塞発症前のメトホルミン内服による脳小血管病に対する神経保護効果

秋山夏葵, 二宮格, 山城貴之, 上村昌寛, 服部頼都, 猪原匡史, 小野寺理, 金澤雅人

臨床神経学 63 ( Suppl. ) S310 - S310 2023年9月

発作性の神経症状を繰り返し、多発する微小出血像を認めた硬膜移植歴を有する39歳男性例

畠山祐樹, 坪口晋太朗, 石黒敬信, 佐治越爾, 畠山公大, 島田斉, 金澤雅人, 小野寺理

臨床神経学 63 ( 9 ) 603 - 603 2023年9月

新潟県,脊髄小脳変性疫学調査-臨床調査個人票による調査

小出眞悟, 本郷祥子, 秋山夏葵, 中村航世, 小野寺理

臨床神経学 63 ( Suppl. ) S297 - S297 2023年9月

【神経変性疾患の眼球運動異常】脊髄小脳変性症の眼球運動の特徴や異常

小出眞悟, 石原智彦, 小野寺理

神経眼科 40 ( 3 ) 222 - 228 2023年9月

【いま新薬で加速する神経変性疾患研究異常タンパク質の構造、凝集のしくみから根本治療の真の標的に迫る】(第1章)タンパク質構造と病態 ALS病態のカギを握る液-液相分離

小出眞悟, 須貝章弘, 小野寺理

実験医学 41 ( 12 ) 1883 - 1889 2023年8月

FUS regulates RAN translation through modulating the G-quadruplex structure of GGGGCC repeat RNA in C9orf72-linked ALS/FTD. 国際誌

Yuzo Fujino, Morio Ueyama, Taro Ishiguro, Daisaku Ozawa, Hayato Ito, Toshihiko Sugiki, Asako Murata, Akira Ishiguro, Tania Gendron, Kohji Mori, Eiichi Tokuda, Tomoya Taminato, Takuya Konno, Akihide Koyama, Yuya Kawabe, Toshihide Takeuchi, Yoshiaki Furukawa, Toshimichi Fujiwara, Manabu Ikeda, Toshiki Mizuno, Hideki Mochizuki, Hidehiro Mizusawa, Keiji Wada, Kinya Ishikawa, Osamu Onodera, Kazuhiko Nakatani, Leonard Petrucelli, Hideki Taguchi, Yoshitaka Nagai

eLife 12 2023年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

Abnormal expansions of GGGGCC repeat sequence in the noncoding region of the C9orf72 gene is the most common cause of familial amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). The expanded repeat sequence is translated into dipeptide repeat proteins (DPRs) by noncanonical repeat-associated non-AUG (RAN) translation. Since DPRs play central roles in the pathogenesis of C9-ALS/FTD, we here investigate the regulatory mechanisms of RAN translation, focusing on the effects of RNA-binding proteins (RBPs) targeting GGGGCC repeat RNAs. Using C9-ALS/FTD model flies, we demonstrated that the ALS/FTD-linked RBP FUS suppresses RAN translation and neurodegeneration in an RNA-binding activity-dependent manner. Moreover, we found that FUS directly binds to and modulates the G-quadruplex structure of GGGGCC repeat RNA as an RNA chaperone, resulting in the suppression of RAN translation in vitro. These results reveal a previously unrecognized regulatory mechanism of RAN translation by G-quadruplex-targeting RBPs, providing therapeutic insights for C9-ALS/FTD and other repeat expansion diseases.

DOI： 10.7554/eLife.84338

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Inappropriate interpretation of non-pathogenic HTRA1 variant as pathogenic. 国際誌

Masahiro Uemura, Sho Kitahara, Taisuke Kato, Hiroaki Nozaki, Shoichiro Ando, Tomohiko Ishihara, Osamu Onodera

Annals of clinical and translational neurology 10 ( 7 ) 1261 - 1262 2023年7月

The clinical application of optimized AT(N) classification in Alzheimer’s clinical syndrome (ACS) and non-ACS conditions

Kensaku Kasuga, Tamao Tsukie, Masataka Kikuchi, Takayoshi Tokutake, Kazuo Washiyama, Soichiro Shimizu, Hiroshi Yoshizawa, Yasuko Kuroha, Ryuji Yajima, Hiroshi Mori, Yasuaki Arakawa, Kiyoshi Onda, Akinori Miyashita, Osamu Onodera, Takeshi Iwatsubo, Takeshi Ikeuchi

Neurobiology of Aging 127 23 - 32 2023年7月

Vegetable and Fruit Intake Frequency and Mortality in Patients With and Without Chronic Kidney Disease: A Hospital-Based Cohort Study. 国際誌

Minako Wakasugi, Akio Yokoseki, Masakazu Wada, Takeshi Momotsu, Kenji Sato, Hiroyuki Kawashima, Kazutoshi Nakamura, Osamu Onodera, Ichiei Narita

Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation 33 ( 4 ) 566 - 574 2023年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVE: Patients with advanced chronic kidney disease (CKD) are generally discouraged from consuming high amounts of vegetables and fruits given the potential risk of hyperkalemia. In the general population, however, lower vegetable and fruit intake is associated with higher mortality. This Japanese hospital-based prospective cohort study including non-CKD and CKD participants examined whether the frequency of vegetable and fruit intake is associated with mortality, and whether the presence of CKD modifies this association. METHODS: Participants were 2,006 patients who visited the outpatient department of a general hospital between June 2008 and December 2016 (55% men; mean age, 69 years). Among these participants, 902 (45%) and 131 (7%) were non-dialysis-dependent patients with CKD and hemodialysis patients, respectively. The frequency of vegetable and fruit intake was determined by a self-report questionnaire using an ordinal scale, "never or rarely," "sometimes," and "every day." Multivariable Cox proportional hazards analysis was conducted, adjusting for potential confounders. RESULTS: Vegetable and fruit intake frequency decreased with worsening CKD stage (P for trend < .001). Baseline serum potassium levels stratified by CKD stage were similar across the three vegetable and fruit intake frequency groups. During a median follow-up of 5.7 years, 561 participants died (47.1/1,000 person-years). Adjusted hazard ratios relative to the "every day" group were 1.25 (95% confidence interval, 1.04-1.52) and 1.60 (95% confidence interval, 1.23-2.08) for the "sometimes" and "never or rarely" groups, respectively, after adjusting for demographic factors, comorbidities, and CKD status. When stratified by CKD status, a similar, albeit non-significant, dose-dependent relationship was observed between vegetable and fruit intake frequency and all-cause mortality irrespective of CKD status, with no effect modification by CKD status (Pinteraction = .69). CONCLUSION: A lower frequency of vegetable and fruit intake is significantly associated with a higher risk of death regardless of CKD status.

DOI： 10.1053/j.jrn.2023.01.011

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[Disseminated herpes zoster complicated by lumbosacral polyradiculoneuritis and fibular neuropathy: A case report].

Kosei Nakamura, Shintaro Tsuboguchi, Itaru Ninomiya, Osamu Ansai, Masato Kanazawa, Osamu Onodera

Rinsho shinkeigaku = Clinical neurology 63 ( 6 ) 359 - 362 2023年6月

記述言語：日本語掲載種別：研究論文（学術雑誌）

A 74-year-old woman who presented with a skin eruption involving the left lateral leg along the L5 dermatome and widespread eruptions on the buttocks and trunk was diagnosed with disseminated herpes zoster (HZ). She also had left lower extremity muscle weakness. The pattern of distribution of muscle weakness and gadolinium-enhanced magnetic resonance imaging findings indicated polyradiculoneuritis mainly affecting the L5 spinal root. Moreover, we observed severe weakness of the left tibialis anterior muscle. Weakness of the other L5 myotomes reduced after antiviral treatment; however, left tibialis anterior muscle weakness persisted. We concluded that lumbosacral polyradiculoneuritis was attributable to varicella-zoster virus (VZV) infection, which also caused fibular neuropathy in this case. Retrograde transport of the VZV may have infected the fibular nerve throughout the sites of skin eruption. It is important to be mindful of simultaneous nerve root and peripheral nerve involvement in cases of motor paralysis associated with HZ infection.

DOI： 10.5692/clinicalneurol.cn-001848

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Progressive conus medullaris lesions are suggestive of intravascular large B-cell lymphoma. 国際誌

Sho Kitahara, Masato Kanazawa, Manabu Natsumeda, Aki Sato, Masanori Ishikawa, Kenju Hara, Hiroyuki Tabe, Kunihiko Makino, Kouichirou Okamoto, Nobuya Fujita, Akiyoshi Kakita, Yukihiko Fuji, Osamu Onodera

European journal of neurology 2023年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND AND PURPOSE: Spinal cord lesions are observed in 40% of all central nervous system lesions in intravascular large B-cell lymphoma (IVLBCL). However, because IVLBCL is a very rare disease, its clinical features are not well defined, which may delay appropriate diagnosis and treatment, whilst the acute to subacute course of brain lesions in patients with IVLBCL is well established. Therefore, this study aimed to clarify the clinical features of spinal cord lesions in patients with IVLBCL. METHODS: The medical records of patients with IVLBCL admitted to our hospital between 2010 and 2020 were searched. The inclusion criteria were preceding neurological symptoms without non-neurological symptoms and pathologically confirmed IVLBCL in various organs. Clinical features of spinal cord involvement in patients with IVLBCL were assessed and distinguished from those of brain involvement. RESULTS: Sixteen consecutive patients with IVLBCL were divided into two groups: six patients with spinal involvement (spinal cord type) and 10 patients with brain involvement (brain type). In the spinal cord type, four patients had chronic progression and two had subacute progression. Acute progression (0% vs. 80.0%) and sudden onset (0% vs. 50.0%) occurred significantly less frequently in the spinal cord than in the brain. All spinal cord lesions involved the conus medullaris. CONCLUSIONS: Spinal cord involvement in IVLBCL has a predominantly chronic progressive course that is exclusive to brain involvement. Conus medullaris lesions are suggestive of IVLBCL and are useful for early and accurate diagnosis and treatment.

DOI： 10.1111/ene.15941

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Oxygen–Glucose Deprived Peripheral Blood Mononuclear Cells Protect Against Ischemic Stroke

Yutaka Otsu, Masahiro Hatakeyama, Takeshi Kanayama, Natsuki Akiyama, Itaru Ninomiya, Kaoru Omae, Taisuke Kato, Osamu Onodera, Masanori Fukushima, Takayoshi Shimohata, Masato Kanazawa

Neurotherapeutics 2023年6月

Preclinical Characterization of the Tau PET Tracer [18F]SNFT-1: Comparison of Tau PET Tracers 査読

Ryuichi Harada, Pradith Lerdsirisuk, Yuki Shimizu, Yuka Yokoyama, Yiqing Du, Kaede Kudo, Michinori Ezura, Yoichi Ishikawa, Ren Iwata, Miho Shidahara, Aiko Ishiki, Akio Kikuchi, Yuya Hatano, Tomohiko Ishihara, Osamu Onodera, Yasushi Iwasaki, Mari Yoshida, Yasuyuki Taki, Hiroyuki Arai, Yukitsuka Kudo, Kazuhiko Yanai, Shozo Furumoto, Nobuyuki Okamura

Journal of Nuclear Medicine jnumed.123.265593 - jnumed.123.265593 2023年6月

Heterogenous Genetic, Clinical, and Imaging Features in Patients with Neuronal Intranuclear Inclusion Disease Carrying NOTCH2NLC Repeat Expansion. 国際誌

Yusran Ady Fitrah, Yo Higuchi, Norikazu Hara, Takayoshi Tokutake, Masato Kanazawa, Kazuhiro Sanpei, Tomone Taneda, Akihiko Nakajima, Shin Koide, Shintaro Tsuboguchi, Midori Watanabe, Junki Fukumoto, Shoichiro Ando, Tomoe Sato, Yohei Iwafuchi, Aki Sato, Hideki Hayashi, Takanobu Ishiguro, Hayato Takeda, Toshiaki Takahashi, Nobuyoshi Fukuhara, Kensaku Kasuga, Akinori Miyashita, Osamu Onodera, Takeshi Ikeuchi

Brain sciences 13 ( 6 ) 2023年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder that is caused by the abnormal expansion of non-coding trinucleotide GGC repeats in NOTCH2NLC. NIID is clinically characterized by a broad spectrum of clinical presentations. To date, the relationship between expanded repeat lengths and clinical phenotype in patients with NIID remains unclear. Thus, we aimed to clarify the genetic and clinical spectrum and their association in patients with NIID. For this purpose, we genetically analyzed Japanese patients with adult-onset NIID with characteristic clinical and neuroimaging findings. Trinucleotide repeat expansions of NOTCH2NLC were examined by repeat-primed and amplicon-length PCR. In addition, long-read sequencing was performed to determine repeat size and sequence. The expanded GGC repeats ranging from 94 to 361 in NOTCH2NLC were found in all 15 patients. Two patients carried biallelic repeat expansions. There were marked heterogenous clinical and imaging features in NIID patients. Patients presenting with cerebellar ataxia or urinary dysfunction had a significantly larger GGC repeat size than those without. This significant association disappeared when these parameters were compared with the total trinucleotide repeat number. ARWMC score was significantly higher in patients who had a non-glycine-type trinucleotide interruption within expanded poly-glycine motifs than in those with a pure poly-glycine expansion. These results suggested that the repeat length and sequence in NOTCH2NLC may partly modify some clinical and imaging features of NIID.

DOI： 10.3390/brainsci13060955

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Nine Hereditary Movement Disorders First Described in Asia: Their History and Evolution. 国際誌

Priya Jagota, Yoshikazu Ugawa, Zakiyah Aldaajani, Norlinah Mohamed Ibrahim, Hiroyuki Ishiura, Yoshiko Nomura, Shoji Tsuji, Cid Diesta, Nobutaka Hattori, Osamu Onodera, Saeed Bohlega, Amir S N AlDin, Shen-Yang Lim, Jee-Young Lee, Beomseok Jeon, Pramod Kumar Pal, Huifang Shang, Shinsuke Fujioka, Prashanth Lingappa Kukkle, Onanong Phokaewvarangkul, Chin-Hsien Lin, Cholpon Shambetova, Roongroj Bhidayasiri

Journal of movement disorders 2023年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Clinical case studies and reporting are important to the discovery of new disorders and the advancement of medical sciences. Both clinicians and basic scientists play equally important roles leading to treatment discoveries for both cures and symptoms. In the field of movement disorders, exceptional observation of patients from clinicians is imperative, not just for phenomenology but also for the variable occurrences of these disorders, along with other signs and symptoms, throughout the day and the disease course. The Movement Disorders in Asia Task Force (TF) was formed to help enhance and promote collaboration and research on movement disorders within the region. As a start, the TF has reviewed the original studies of the movement disorders that were preliminarily described in the region. These include nine disorders that were first described in Asia - Segawa disease, PARK-Parkin, X-linked dystonia-parkinsonism (XDP), dentatorubral-pallidoluysian atrophy (DRPLA), Woodhouse-Sakati syndrome, benign adult familial myoclonic epilepsy (BAFME), Kufor-Rakeb disease, tremulous dystonia associated with mutation of the calmodulin-binding transcription activator 2 (CAMTA2) gene, and paroxysmal kinesigenic dyskinesia (PKD). We hope that the information provided will honor the original researchers and help us learn and understand how earlier neurologists and basic scientists together discovered new disorders and made advances in the field, which impact us all to this day.

DOI： 10.14802/jmd.23065

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Accuracy of a machine learning method based on structural and locational information from AlphaFold2 for predicting the pathogenicity of TARDBP and FUS gene variants in ALS

Yuya Hatano, Tomohiko Ishihara, Osamu Onodera

BMC Bioinformatics 24 ( 1 ) 2023年5月

掲載種別：研究論文（学術雑誌）出版者・発行元：Springer Science and Business Media LLC

Abstract

Background

In the sporadic form of amyotrophic lateral sclerosis (ALS), the pathogenicity of rare variants in the causative genes characterizing the familial form remains largely unknown. To predict the pathogenicity of such variants, in silico analysis is commonly used. In some ALS causative genes, the pathogenic variants are concentrated in specific regions, and the resulting alterations in protein structure are thought to significantly affect pathogenicity. However, existing methods have not taken this issue into account. To address this, we have developed a technique termed MOVA (method for evaluating the pathogenicity of missense variants using AlphaFold2), which applies positional information for structural variants predicted by AlphaFold2. Here we examined the utility of MOVA for analysis of several causative genes of ALS.

Methods

We analyzed variants of 12 ALS-related genes (TARDBP, FUS, SETX, TBK1, OPTN, SOD1, VCP, SQSTM1, ANG, UBQLN2, DCTN1, and CCNF) and classified them as pathogenic or neutral. For each gene, the features of the variants, consisting of their positions in the 3D structure predicted by AlphaFold2, pLDDT score, and BLOSUM62 were trained into a random forest and evaluated by the stratified fivefold cross validation method. We compared how accurately MOVA predicted mutant pathogenicity with other in silico prediction methods and evaluated the prediction accuracy at TARDBP and FUS hotspots. We also examined which of the MOVA features had the greatest impact on pathogenicity discrimination.

Results

MOVA yielded useful results (AUC ≥ 0.70) for TARDBP, FUS, SOD1, VCP, and UBQLN2 of 12 ALS causative genes. In addition, when comparing the prediction accuracy with other in silico prediction methods, MOVA obtained the best results among those compared for TARDBP, VCP, UBQLN2, and CCNF. MOVA demonstrated superior predictive accuracy for the pathogenicity of mutations at hotspots of TARDBP and FUS. Moreover, higher accuracy was achieved by combining MOVA with REVEL or CADD. Among the features of MOVA, the x, y, and z coordinates performed the best and were highly correlated with MOVA.

Conclusions

MOVA is useful for predicting the virulence of rare variants in which they are concentrated at specific structural sites, and for use in combination with other prediction methods.

DOI： 10.1186/s12859-023-05338-5

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その他リンク： https://link.springer.com/article/10.1186/s12859-023-05338-5/fulltext.html

V180I genetic Creutzfeldt-Jakob disease: Severe degeneration of the inferior olivary nucleus in an autopsied patient with identification of the M2T prion strain. 国際誌

Midori Watanabe, Kosei Nakamura, Rie Saito, Atsuko Takeuchi, Tetsuya Takahashi, Tetsuyuki Kitamoto, Osamu Onodera, Akiyoshi Kakita

Neuropathology : official journal of the Japanese Society of Neuropathology 2023年5月

記述言語：英語

Genetic Creutzfeldt-Jakob disease (gCJD) with a V180I mutation (V180I gCJD) is the most common type of gCJD in Japan, characterized by an older age at onset, slower progression, and moderate to severe cortical degeneration with spongiform changes and sparing of the brainstem and cerebellum. Degeneration of the inferior olivary nucleus (IO) is rarely observed in patients with CJD but is known to occur in fatal familial insomnia (FFI) and MM2-thalamic-type sporadic CJD (sCJD-MM2T) involving type 2 prion protein (M2T prion). Here we report on an 81-year-old Japanese woman who initially developed depressive symptoms followed by progressive cognitive impairment, myoclonus, and hallucinations and died after a clinical course of 23 months. Insomnia was not evident. Genetic analysis of the prion protein (PrP) identified a V180I mutation with methionine/valine heterozygosity at codon 129. Pathologic analysis demonstrated extensive spongiform degeneration, neuronal loss in the cortices, and weak synaptic-type PrP deposition. Except for IO degeneration, the clinicopathologic features and Western blotting PrP band pattern were compatible with those of previously reported V180I gCJD cases. Quantitative analysis revealed that the neuronal density of the IO, especially in the dorsal area, was considerably reduced to the same extent as that of a patient with sCJD-MM2T but preserved in other patients with V180I gCJD and sCJD-MM1 (this patient, 2.3 ± 0.53/mm2 ; a patient with sCJD-MM2T, 4.2 ± 2; a patient with V180I gCJD, 60.5 ± 9.3; and a patient with sCJD-MM1, 84.5 ± 17.9). Use of the protein misfolding cyclic amplification (PMCA) method confirmed the presence of the M2T prion strain, suggesting that the latter might be associated with IO degeneration in V180I gCJD. Autopsy studies are necessary to better understand the nature of CJD, since even if patients present with the common clinical picture, pathologic analysis might provide new insights, as was the case here.

DOI： 10.1111/neup.12908

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Genetic factors affecting survival in Japanese patients with sporadic amyotrophic lateral sclerosis: a genome-wide association study and verification in iPSC-derived motor neurons from patients. 国際誌

Ryoichi Nakamura, Genki Tohnai, Masahiro Nakatochi, Naoki Atsuta, Hirohisa Watanabe, Daisuke Ito, Masahisa Katsuno, Akihiro Hirakawa, Yuishin Izumi, Mitsuya Morita, Takehisa Hirayama, Osamu Kano, Kazuaki Kanai, Nobutaka Hattori, Akira Taniguchi, Naoki Suzuki, Masashi Aoki, Ikuko Iwata, Ichiro Yabe, Kazumoto Shibuya, Satoshi Kuwabara, Masaya Oda, Rina Hashimoto, Ikuko Aiba, Tomohiko Ishihara, Osamu Onodera, Toru Yamashita, Koji Abe, Kouichi Mizoguchi, Toshio Shimizu, Yoshio Ikeda, Takanori Yokota, Kazuko Hasegawa, Fumiaki Tanaka, Kenji Nakashima, Ryuji Kaji, Jun-Ichi Niwa, Manabu Doyu, Chikashi Terao, Shiro Ikegawa, Koki Fujimori, Shiho Nakamura, Fumiko Ozawa, Satoru Morimoto, Kazunari Onodera, Takuji Ito, Yohei Okada, Hideyuki Okano, Gen Sobue

Journal of neurology, neurosurgery, and psychiatry 94 ( 10 ) 816 - 824 2023年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Several genetic factors are associated with the pathogenesis of sporadic amyotrophic lateral sclerosis (ALS) and its phenotypes, such as disease progression. Here, in this study, we aimed to identify the genes that affect the survival of patients with sporadic ALS. METHODS: We enrolled 1076 Japanese patients with sporadic ALS with imputed genotype data of 7 908 526 variants. We used Cox proportional hazards regression analysis with an additive model adjusted for sex, age at onset and the first two principal components calculated from genotyped data to conduct a genome-wide association study. We further analysed messenger RNA (mRNA) and phenotype expression in motor neurons derived from induced pluripotent stem cells (iPSC-MNs) of patients with ALS. RESULTS: Three novel loci were significantly associated with the survival of patients with sporadic ALS-FGF1 at 5q31.3 (rs11738209, HR=2.36 (95% CI, 1.77 to 3.15), p=4.85×10-9), THSD7A at 7p21.3 (rs2354952, 1.38 (95% CI, 1.24 to 1.55), p=1.61×10-8) and LRP1 at 12q13.3 (rs60565245, 2.18 (95% CI, 1.66 to 2.86), p=2.35×10-8). FGF1 and THSD7A variants were associated with decreased mRNA expression of each gene in iPSC-MNs and reduced in vitro survival of iPSC-MNs obtained from patients with ALS. The iPSC-MN in vitro survival was reduced when the expression of FGF1 and THSD7A was partially disrupted. The rs60565245 was not associated with LRP1 mRNA expression. CONCLUSIONS: We identified three loci associated with the survival of patients with sporadic ALS, decreased mRNA expression of FGF1 and THSD7A and the viability of iPSC-MNs from patients. The iPSC-MN model reflects the association between patient prognosis and genotype and can contribute to target screening and validation for therapeutic intervention.

DOI： 10.1136/jnnp-2022-330851

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Machine Learning Approach for the Prediction of Age-Specific Probability of SCA3 and DRPLA by Survival Curve Analysis

Yuya Hatano, Tomohiko Ishihara, Sachiko Hirokawa, Osamu Onodera

Neurology Genetics 9 ( 3 ) e200075 - e200075 2023年5月

掲載種別：研究論文（学術雑誌）出版者・発行元：Ovid Technologies (Wolters Kluwer Health)

Background and Objectives

As the number of repeats in the expansion increases, polyglutamine diseases tend to show at a younger age. From this relationship, attempts have been made to predict age at onset by parametric survival analysis. However, a method for a more accurate prediction has been desirable. In this study, we examined 2 methods for survival analysis using machine learning and 6 conventional methods for parametric survival analysis of spinocerebellar ataxia (SCA)3 and dentatorubral-pallidoluysian atrophy (DRPLA).

Methods

We compared the performance of 2 machine learning methods of survival analysis (random survival forest [RSF] and DeepSurv) and 6 methods of parametric survival analysis (Weibull, exponential, Gaussian, logistic, loglogistic, and log Gaussian). Training and evaluation were performed using the leave-one-out cross-validation method, and evaluation criteria included root mean squared error (RMSE), mean absolute error (MAE), and the integrated Brier score. The latter was used as the primary end point, and the survival analysis model yielding the best result was used to predict the asymptomatic probability.

Results

Among the models examined, the RSF and DeepSurv machine learning methods had a higher prediction accuracy than the parametric methods of survival analysis. For both SCA3 and DRPLA, RSF had a higher accuracy than DeepSurv for the assessment of RMSE (SCA3: 7.37, DRPLA: 10.78), MAE (SCA3: 5.52, DRPLA: 8.17), and the integrated Brier score (SCA3: 0.05, DRPLA: 0.077). Using RSF, we determined the age-specific probability distribution of age at onset based on CAG repeat size and current age.

Discussion

In this study, we have demonstrated the superiority of machine learning methods for predicting age at onset of SCA3 and DRPLA using survival analysis. Such accurate prediction of onset will be useful for genetic counseling of carriers and for devising methods to verify the effects of interventions for unaffected individuals.

DOI： 10.1212/nxg.0000000000200075

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Genome-wide association study identifies a new susceptibility locus in PLA2G4C for Multiple System Atrophy. 国際誌

Yasuo Nakahara, Jun Mitsui, Hidetoshi Date, Kristine Joyce Porto, Yasuhiro Hayashi, Atsushi Yamashita, Yoshio Kusakabe, Takashi Matsukawa, Hiroyuki Ishiura, Tsutomu Yasuda, Atsushi Iwata, Jun Goto, Yaeko Ichikawa, Yoshio Momose, Yuji Takahashi, Tatsushi Toda, Rikifumi Ohta, Jun Yoshimura, Shinichi Morishita, Emil K Gustavsson, Darren Christy, Melissa Maczis, Matthew J Farrer, Han-Joon Kim, Sung-Sup Park, Beomseok Jeon, Jin Zhang, Weihong Gu, Sonja W Scholz, Andrew B Singleton, Henry Houlden, Ichiro Yabe, Hidenao Sasaki, Masaaki Matsushima, Hiroshi Takashima, Akio Kikuchi, Masashi Aoki, Kenju Hara, Akiyoshi Kakita, Mitsunori Yamada, Hitoshi Takahashi, Osamu Onodera, Masatoyo Nishizawa, Hirohisa Watanabe, Mizuki Ito, Gen Sobue, Kinya Ishikawa, Hidehiro Mizusawa, Kazuaki Kanai, Satoshi Kuwabara, Kimihito Arai, Shigeru Koyano, Yoshiyuki Kuroiwa, Kazuko Hasegawa, Tatsuhiko Yuasa, Kenichi Yasui, Kenji Nakashima, Hijiri Ito, Yuishin Izumi, Ryuji Kaji, Takeo Kato, Susumu Kusunoki, Yasushi Osaki, Masahiro Horiuchi, Ken Yamamoto, Mihoko Shimada, Taku Miyagawa, Yosuke Kawai, Nao Nishida, Katsushi Tokunaga, Alexandra Dürr, Alexis Brice, Alessandro Filla, Thomas Klockgether, Ullrich Wüllner, Caroline M Tanner, Walter A Kukull, Virginia M-Y Lee, Eliezer Masliah, Phillip A Low, Paola Sandroni, Laurie Ozelius, Tatiana Foroud, Shoji Tsuji

medRxiv : the preprint server for health sciences 2023年5月

記述言語：英語

To elucidate the molecular basis of multiple system atrophy (MSA), a neurodegenerative disease, we conducted a genome-wide association study (GWAS) in a Japanese MSA case/control series followed by replication studies in Japanese, Korean, Chinese, European and North American samples. In the GWAS stage rs2303744 on chromosome 19 showed a suggestive association ( P = 6.5 × 10 -7 ) that was replicated in additional Japanese samples ( P = 2.9 × 10 -6 . OR = 1.58; 95% confidence interval, 1.30 to 1.91), and then confirmed as highly significant in a meta-analysis of East Asian population data ( P = 5.0 × 10 -15 . Odds ratio= 1.49; 95% CI 1.35 to 1.72). The association of rs2303744 with MSA remained significant in combined European/North American samples ( P =0.023. Odds ratio=1.14; 95% CI 1.02 to 1.28) despite allele frequencies being quite different between these populations. rs2303744 leads to an amino acid substitution in PLA2G4C that encodes the cPLA2γ lysophospholipase/transacylase. The cPLA2γ-Ile143 isoform encoded by the MSA risk allele has significantly decreased transacylase activity compared with the alternate cPLA2γ-Val143 isoform that may perturb membrane phospholipids and α-synuclein biology.

DOI： 10.1101/2023.05.02.23289328

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High-dose ubiquinol supplementation in multiple-system atrophy: a multicentre, randomised, double-blinded, placebo-controlled phase 2 trial. 国際誌

Jun Mitsui, Takashi Matsukawa, Yukari Uemura, Takuya Kawahara, Ayaka Chikada, Kristine Joyce L Porto, Hiroya Naruse, Masaki Tanaka, Hiroyuki Ishiura, Tatsushi Toda, Haruko Kuzuyama, Mari Hirano, Ikue Wada, Toshio Ga, Takashi Moritoyo, Yuji Takahashi, Hidehiro Mizusawa, Kinya Ishikawa, Takanori Yokota, Satoshi Kuwabara, Nobukatsu Sawamoto, Ryosuke Takahashi, Koji Abe, Tomohiko Ishihara, Osamu Onodera, Dai Matsuse, Ryo Yamasaki, Jun-Ichi Kira, Masahisa Katsuno, Ritsuko Hanajima, Katsuhisa Ogata, Hiroshi Takashima, Masaaki Matsushima, Ichiro Yabe, Hidenao Sasaki, Shoji Tsuji

EClinicalMedicine 59 101920 - 101920 2023年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Functionally impaired variants of COQ2, encoding an enzyme in biosynthesis of coenzyme Q10 (CoQ10), were found in familial multiple system atrophy (MSA) and V393A in COQ2 is associated with sporadic MSA. Furthermore, reduced levels of CoQ10 have been demonstrated in MSA patients. METHODS: This study was a multicentre, randomised, double-blinded, placebo-controlled phase 2 trial. Patients with MSA were randomly assigned (1:1) to either ubiquinol (1500 mg/day) or placebo. The primary efficacy outcome was the change in the unified multiple system atrophy rating scale (UMSARS) part 2 at 48 weeks. Efficacy was assessed in all patients who completed at least one efficacy assessment (full analysis set). Safety analyses included patients who completed at least one dose of investigational drug. This trial is registered with UMIN-CTR (UMIN000031771), where the drug name of MSA-01 was used to designate ubiquinol. FINDINGS: Between June 26, 2018, and May 27, 2019, 139 patients were enrolled and randomly assigned to the ubiquinol group (n = 69) or the placebo group (n = 70). A total of 131 patients were included in the full analysis set (63 in the ubiquinol group; 68 in the placebo group). This study met the primary efficacy outcome (least square mean difference in UMSARS part 2 score (-1.7 [95% CI, -3.2 to -0.2]; P = 0.023)). The ubiquinol group also showed better secondary efficacy outcomes (Barthel index, Scale for the Assessment and Rating of Ataxia, and time required to walk 10 m). Rates of adverse events potentially related to the investigational drug were comparable between ubiquinol (n = 15 [23.8%]) and placebo (n = 21 [30.9%]). INTERPRETATION: High-dose ubiquinol was well-tolerated and led to a significantly smaller decline of UMSARS part 2 score compared with placebo. FUNDING: Japan Agency for Medical Research and Development.

DOI： 10.1016/j.eclinm.2023.101920

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Parkinson症候群の治療法開発の最前線進行性核上性麻痺の新規治療法開発どのように臨床試験を成功させるか

金澤雅人, 春日健作, 島田斉, 池内健, 小野寺理

神経治療学 40 ( 3 ) 259 - 265 2023年5月

Parkinson症候群の治療法開発の最前線進行性核上性麻痺の新規治療法開発どのように臨床試験を成功させるか

金澤雅人, 春日健作, 島田斉, 池内健, 小野寺理

神経治療学 40 ( 3 ) 259 - 265 2023年5月

A human induced pluripotent stem cell model from a patient with hereditary cerebral small vessel disease carrying a heterozygous R302Q mutation in HTRA1. 国際誌

Emi Qian, Masahiro Uemura, Hiroya Kobayashi, Shiho Nakamura, Fumiko Ozawa, Sho Yoshimatsu, Mitsuru Ishikawa, Osamu Onodera, Satoru Morimoto, Hideyuki Okano

Inflammation and regeneration 43 ( 1 ) 23 - 23 2023年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is an inherited cerebral small vessel disease (CSVD) caused by biallelic mutations in the high-temperature requirement serine peptidase A1 (HTRA1) gene. Even heterozygous mutations in HTRA1 are recently revealed to cause cardinal clinical features of CSVD. Here, we report the first establishment of a human induced pluripotent stem cell (hiPSC) line from a patient with heterozygous HTRA1-related CSVD. Peripheral blood mononuclear cells (PBMCs) were reprogrammed by the transfection of episomal vectors encoding human OCT3/4 (POU5F1), SOX2, KLF4, L-MYC, LIN28, and a murine dominant-negative mutant of p53 (mp53DD). The established iPSCs had normal morphology as human pluripotent stem cells and normal karyotype (46XX). Moreover, we found that the HTRA1 missense mutation (c.905G>A, p.R302Q) was heterozygous. These iPSCs expressed pluripotency-related markers and had the potential to differentiate into all three germ layers in vitro. HTRA1 and the supposed disease-associated gene NOG were differentially expressed in the patient iPSCs at mRNA levels compared to those of control lines. The iPSC line would facilitate in vitro research for understanding the cellular pathomechanisms caused by the HTRA1 mutation including its dominant-negative effect.

DOI： 10.1186/s41232-023-00273-7

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遺伝性痙性対麻痺を呈しGTP cyclohydrolase 1ヘテロ接合性変異を認めた1剖検例

本郷祥子, 他田真理, 池田哲彦, 小澤哲夫, 劉李きん, 宮下哲典, 池内健, 小野寺理, 中島孝, 柿田明美

信州医学雑誌 71 ( 2 ) 128 - 129 2023年4月

遺伝性痙性対麻痺を呈しGTP cyclohydrolase 1ヘテロ接合性変異を認めた1剖検例

本郷祥子, 他田真理, 池田哲彦, 小澤哲夫, 劉李きん, 宮下哲典, 池内健, 小野寺理, 中島孝, 柿田明美

信州医学雑誌 71 ( 2 ) 128 - 129 2023年4月

初期にCastleman病が疑われ特徴的な神経伝導検査所見を呈した61歳男性例

畠山祐樹, 坪口晋太朗, 石黒敬信, 佐治越爾, 細島康宏, 片桐隆幸, 金澤雅人, 小野寺理

臨床神経学 63 ( 4 ) 240 - 240 2023年4月

Novel Partial Deletions, Frameshift and Missense Mutations of CSF1R in Patents with CSF1R-Related Leukoencephalopathy. 国際誌

Takanobu Ishiguro, Takuya Konno, Norikazu Hara, Bin Zhu, Satoshi Okada, Mamoru Shibata, Reiko Saika, Takaya Kitano, Megumi Toko, Tomohisa Nezu, Yuka Hama, Tomoya Kawazoe, Ikuko Takahashi-Iwata, Ichiro Yabe, Kota Sato, Hayato Takeda, Shintaro Toda, Jin Nishimiya, Toshiyuki Teduka, Hiroaki Nozaki, Kensaku Kasuga, Akinori Miyashita, Osamu Onodera, Takeshi Ikeuchi

European journal of neurology 30 ( 7 ) 1861 - 1870 2023年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: CSF1R-related leukoencephalopathy is an adult-onset leukoencephalopathy caused by mutations in CSF1R. The present study aimed to explore the broader genetic spectrum of CSF1R-related leukoencephalopathy in association with clinical and imaging features. METHODS: Mutational analysis of CSF1R was performed for 100 consecutive patients with adult-onset leukoencephalopathy. Sequence and copy number variation (CNV) analyses of CSF1R were performed. The genomic ranges of the deletions were determined by long-read sequencing. Ligand-dependent autophosphorylation of CSF1R was examined in cells expressing the CSF1R mutants identified in this study. RESULTS: We identified CSF1R mutations in 15 patients, accounting for 15% of the adult-onset leukoencephalopathy cases. Seven novel and five previously reported CSF1R mutations were identified. The novel mutations, including three missense and one in-frame 3-bp deletion, were located in the tyrosine kinase domain (TKD) of CSF1R. Functional assays revealed that none of the novel mutations in the TKD showed autophosphorylation of CSF1R. We identified two partial deletions of CSF1R that resulted in the lack of the C-terminal region, including the distal TKD, in two patients. Variable clinical features including cognitive impairment, psychiatric symptoms, and gait disturbance were observed. Various degrees of the white matter lesions and corpus callosum abnormalities on MRI and characteristic calcifications on CT were observed as imaging features. CONCLUSIONS: Our results highlighted the importance of examining the CNV of CSF1R even when Sanger or exome sequencing reveal no CSF1R mutations. Genetic examination of sequences and CNV analyses of CSF1R are recommended for an accurate diagnosis of CSF1R-related leukoencephalopathy.

DOI： 10.1111/ene.15796

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脳血管造影検査後の発熱・意識障害で診断された神経核内封入体病(NIID)の一例

小出伸, 坪口晋太朗, 二宮格, 齋藤太希, 石黒敬信, 佐治越爾, 鈴木倫明, 金澤雅人, 小野寺理

臨床神経学 63 ( 3 ) 180 - 180 2023年3月

【ALS-どこまでわかり,どこまで治るか】原因と発症機序 TDP-43

小出眞悟, 須貝章弘, 小野寺理

Clinical Neuroscience 41 ( 3 ) 338 - 341 2023年3月

Cataract Surgery and Chronic Kidney Disease: A Hospital-based Prospective Cohort Study

Minako Wakasugi, Akio Yokoseki, Masakazu Wada, Takaiko Yoshino, Takeshi Momotsu, Kenji Sato, Hiroyuki Kawashima, Kazutoshi Nakamura, Takeo Fukuchi, Osamu Onodera, Ichiei Narita

Internal Medicine 2023年

Implications of miRNAs dysregulation in amyotrophic lateral sclerosis: Challenging for clinical applications. 国際誌

Yuka Koike, Osamu Onodera

Frontiers in neuroscience 17 1131758 - 1131758 2023年

記述言語：英語掲載種別：研究論文（学術雑誌）

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective degeneration of upper and lower motor neurons. Currently, there are no effective biomarkers and fundamental therapies for this disease. Dysregulation in RNA metabolism plays a critical role in the pathogenesis of ALS. With the contribution of Next Generation Sequencing, the functions of non-coding RNAs (ncRNAs) have gained increasing interests. Especially, micro RNAs (miRNAs), which are tissue-specific small ncRNAs of about 18-25 nucleotides, have emerged as key regulators of gene expression to target multiple molecules and pathways in the central nervous system (CNS). Despite intensive recent research in this field, the crucial links between ALS pathogenesis and miRNAs remain unclear. Many studies have revealed that ALS-related RNA binding proteins (RBPs), such as TAR DNA-binding protein 43 (TDP-43) and fused in sarcoma/translocated in liposarcoma (FUS), regulate miRNAs processing in both the nucleus and cytoplasm. Of interest, Cu2+/Zn2+ superoxide dismutase (SOD1), a non-RBP associated with familial ALS, shows partially similar properties to these RBPs via the dysregulation of miRNAs in the cellular pathway related to ALS. The identification and validation of miRNAs are important to understand the physiological gene regulation in the CNS, and the pathological implications in ALS, leading to a new avenue for early diagnosis and gene therapies. Here, we offer a recent overview regarding the mechanism underlying the functions of multiple miRNAs across TDP-43, FUS, and SOD1 with the context of cell biology, and challenging for clinical applications in ALS.

DOI： 10.3389/fnins.2023.1131758

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Regeneration of the cerebral cortex by direct chemical reprogramming of macrophages into neuronal cells in acute ischemic stroke. 国際誌

Itaru Ninomiya, Akihide Koyama, Yutaka Otsu, Osamu Onodera, Masato Kanazawa

Frontiers in cellular neuroscience 17 1225504 - 1225504 2023年

記述言語：英語掲載種別：研究論文（学術雑誌）

Theoretically, direct chemical reprogramming of somatic cells into neurons in the infarct area represents a promising regenerative therapy for ischemic stroke. Previous studies have reported that human fibroblasts and astrocytes transdifferentiate into neuronal cells in the presence of small molecules without introducing ectopic transgenes. However, the optimal combination of small molecules for the transdifferentiation of macrophages into neurons has not yet been determined. The authors hypothesized that a combination of small molecules could induce the transdifferentiation of monocyte-derived macrophages into neurons and that the administration of this combination may be a regenerative therapy for ischemic stroke because monocytes and macrophages are directly involved in the ischemic area. Transcriptomes and morphologies of the cells were compared before and after stimulation using RNA sequencing and immunofluorescence staining. Microscopic analyses were also performed to identify cell markers and evaluate functional recovery by blinded examination following the administration of small molecules after ischemic stroke in CB-17 mice. In this study, an essential combination of six small molecules [CHIR99021, Dorsomorphin, Forskolin, isoxazole-9 (ISX-9), Y27632, and DB2313] that transdifferentiated monocyte-derived macrophages into neurons in vitro was identified. Moreover, administration of six small molecules after cerebral ischemia in model animals generated a new neuronal layer in the infarct cortex by converting macrophages into neuronal cells, ultimately improving neurological function. These results suggest that altering the transdifferentiation of monocyte-derived macrophages by the small molecules to adjust their adaptive response will facilitate the development of regenerative therapies for ischemic stroke.

DOI： 10.3389/fncel.2023.1225504

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SYNE1-ataxia: clinicopathologic features of an autopsied patient with novel compound heterozygous mutations

Rie Saito, Norikazu Hara, Mari Tada, Masatoshi Wakabayashi, Akinori Miyashita, Masatoyo Nishizawa, Osamu Onodera, Takeshi Ikeuchi, Akiyoshi Kakita

Journal of Neuropathology & Experimental Neurology 2022年12月

Deep learning classification of urinary sediment crystals with optimal parameter tuning. 国際誌

Takahiro Nagai, Osamu Onodera, Shujiro Okuda

Scientific reports 12 ( 1 ) 21178 - 21178 2022年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

The examination of urinary sediment crystals, the sedimentary components of urine, is useful in screening tests, and is always performed in medical examinations. The examination of urinary sediment crystals is typically done by classifying them under a microscope. Although automated analyzers are commercially available, manual classification is required, which is time-consuming and varies depending on the technologist performing the test and the laboratory. A set of test images was created, consisting of training, validation, and test images. The training images were transformed and augmented using various methods. The test images were classified to determine the patterns that could be correctly classified. Convolutional neural networks were used for training. Furthermore, we also considered the case where the crystal subcategories were not treated as separate. Learning with all parameters except the random cropping parameter showed the highest accuracy value. Treating the subcategories together or separately did not seem to affect the accuracy value. The accuracy of the best pattern was 0.918. When matched to a real-world case, the percentage of correct answers was 88%. Although the number of images was limited, good results were obtained in the classification of crystal images with optimal parameter tuning. The parameter optimization performed in this study can be used as a reference for future studies, with the goal of image classification by deep learning in clinical practice.

DOI： 10.1038/s41598-022-25385-x

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High frequency ofHTRA1ANDABCC6mutations in Japanese patients with adult-onset cerebral small vessel disease

Masahiro Uemura, Yuya Hatano, Hiroaki Nozaki, Shoichiro Ando, Hajime Kondo, Akira Hanazono, Akira Iwanaga, Hiroyuki Murota, Yosuke Osakada, Masato Osaki, Masato Kanazawa, Mitsuyasu Kanai, Yoko Shibata, Reiko Saika, Tadashi Miyatake, Hitoshi Aizawa, Takeshi Ikeuchi, Hidekazu Tomimoto, Ikuko Mizuta, Toshiki Mizuno, Tomohiko Ishihara, Osamu Onodera

Journal of Neurology, Neurosurgery & Psychiatry jnnp - 2022 2022年10月

掲載種別：研究論文（学術雑誌）出版者・発行元：BMJ

Background

This study aimed to clarify the frequency and clinical features of monogenic cerebral small vessel disease (mgCSVD) among patients with adult-onset severe CSVD in Japan.

Methods

This study included patients with adult-onset severe CSVD with an age of onset ≤55 years (group 1) or >55 years and with a positive family history (group 2). After conducting conventional genetic tests forNOTCH3andHTRA1, whole-exome sequencing was performed on undiagnosed patients. Patients were divided into two groups according to the results of the genetic tests: monogenic and undetermined. The clinical and imaging features were compared between the two groups.

Results

Group 1 and group 2 included 75 and 31 patients, respectively. In total, 30 patients hadNOTCH3mutations, 11 patients hadHTRA1mutations, 6 patients hadABCC6mutations, 1 patient had aTREX1mutation, 1 patient had aCOL4A1mutation and 1 patient had aCOL4A2mutation. The total frequency of mutations inNOTCH3,HTRA1andABCC6was 94.0% in patients with mgCSVD. In group 1, the frequency of a family history of first relatives, hypertension and multiple lacunar infarctions (LIs) differed significantly between the two groups (monogenic vs undetermined; family history of first relatives, 61.0% vs 25.0%, p=0.0015; hypertension, 34.1% vs 63.9%, p=0.0092; multiple LIs, 87.8% vs 63.9%, p=0.0134).

Conclusions

More than 90% of mgCSVDs were diagnosed by screening forNOTCH3,HTRA1andABCC6. The target sequences for these three genes may efficiently diagnose mgCSVD in Japanese patients.

DOI： 10.1136/jnnp-2022-329917

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Patients with heterozygous HTRA1-related cerebral small vessel disease misdiagnosed with other diseases: Two case reports 査読

Sho Kitahara, Shintaro Tsuboguchi, Masahiro Uemura, Hiroaki Nozaki, Masato Kanazawa, Osamu Onodera

Clinical Neurology and Neurosurgery 2022年10月

脳梗塞に対する低酸素低糖刺激末梢血単核球投与による脳内変化

金山武史, 畠山公大, 大津裕, 秋山夏葵, 二宮格, 小野寺理, 下畑享良, 金澤雅人

脳循環代謝 34 ( 1 ) 154 - 154 2022年10月

Biallelic COX10 Mutations and PMP22 Deletion in a Family With Leigh Syndrome and Hereditary Neuropathy With Liability to Pressure Palsy

Yasuko Kuroha, Takanobu Ishiguro, Mari Tada, Norikazu Hara, Kei Murayama, Izumi Kawachi, Kensaku Kasuga, Akinori Miyashita, Arika Hasegawa, Tetsuya Takahashi, Nae Matsubara, Osamu Onodera, Akiyoshi Kakita, Ryoko Koike, Takeshi Ikeuchi

Neurology Genetics 8 ( 5 ) e200030 - e200030 2022年10月

掲載種別：研究論文（学術雑誌）出版者・発行元：Ovid Technologies (Wolters Kluwer Health)

Objectives

Leigh syndrome is a progressive encephalopathy characterized by symmetrical lesions in brain. This study aimed to investigate the clinicopathologic and genetic characteristics of a family with Leigh syndrome and hereditary neuropathy with liability to pressure palsy (HNPP).

Methods

Data from a Japanese family's clinical features, MRIs, muscle biopsy, and an autopsy were analyzed. A whole-exome sequence was performed, as well as real-time PCR analysis to determine copy number variations and Western blot analyses.

Results

The proband and her 2 siblings developed spastic paraplegia and mental retardation during childhood. The proband and her sister had peripheral neuropathy, whereas their father developed compression neuropathy. Leigh encephalopathy was diagnosed neuropathologically. Brain MRI revealed changes in cerebral white matter as well as multiple lesions in the brainstem and cerebellum. Muscle biopsy revealed type 2 fiber uniformity and decreased staining of cytochrome c oxidase. The COX10 missense mutation was identified through whole-exome sequence. A 1.4-Mb genomic deletion extending from intron 5 of COX10 to PMP22 was detected.

Discussion

These findings suggest that in this family, Leigh syndrome is associated with a mitochondrial respiratory chain complex IV deficiency caused by biallelic COX10 mutations coexisting with HNPP caused by heterozygous PMP22 deletion.

DOI： 10.1212/nxg.0000000000200030

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Dysarthria-facial paresis syndrome due to long insular artery infarction

Ryutaro Hanyu, Shintaro Tsuboguchi, Itaru Ninomiya, Takanobu Ishiguro, Takuya Konno, Masato Kanazawa, Osamu Onodera

Journal of the Neurological Sciences 120456 - 120456 2022年10月

The CAG repeat length of CACNA1A in both alleles affects the age of onset of SCA6(タイトル和訳中)

Hatano Yuya, Ishihara Tomohiko, Hirokawa Sachiko, Onodera Osamu

臨床神経学 62 ( Suppl. ) S364 - S364 2022年10月

神経症状で初発する血管内大細胞型B細胞リンパ腫の臨床的特徴と診断方法に関する検討

北原匠, 金澤雅人, 徳武孝充, 棗田学, 佐藤晶, 石川正典, 原賢寿, 田部浩行, 牧野邦比古, 藤田信也, 岡本浩一郎, 柿田明美, 藤井幸彦, 小野寺理

臨床神経学 62 ( Suppl. ) S272 - S272 2022年10月

パーキンソン症候群の治療法開発の最前線 PSPの新規治療法開発どのように臨床試験を成功させるか

金澤雅人, 春日健作, 島田斉, 池内健, 小野寺理

神経治療学 39 ( 6 ) S118 - S118 2022年10月

日本人小脳失調症患者におけるRFC1のACAGG反復モチーフの拡大(Expansion of the ACAGG repeat motif in RFC1 in Japanese patients with cerebellar ataxia)

Koide Shingo, Ishihara Tomohiko, Hirokawa Sachiko, Sakakibara Satoko, Aiba Ikuko, Onodera Osamu

臨床神経学 62 ( Suppl. ) S364 - S364 2022年10月

Importance of the Q/N-rich segment for protein stability of endogenous mouse TDP-43. 国際誌

Toshiya Sato, Kanako Oda, Seiko Sakai, Rika Kato, Saori Yamamori, Makoto Itakura, Yoshio Kodera, Masatoyo Nishizawa, Toshikuni Sasaoka, Osamu Onodera, Minesuke Yokoyama

Scientific reports 12 ( 1 ) 14923 - 14923 2022年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

TAR DNA-binding protein 43 kDa (TDP-43), a nuclear protein, plays an important role in the molecular pathogenesis of amyotrophic lateral sclerosis (ALS). The long-disordered C-terminal region (CTR) of TDP-43 is known to be aggregation-prone and a hotspot for ALS mutations, so elucidation of the physiological function of CTR will provide insights into the pathogenesis of ALS. The CTR has two Gly, aromatic, and Ser-rich (GaroS) segments and an amyloidogenic core divided into a hydrophobic patch (HP) and a Gln/Asn (Q/N)-rich segment. Although TDP-43 lacking the CTR is known to be unstable, as observed in knock-in mice, it is unclear which of these segments contributes to the stability of TDP-43. Here, we generated 12 mouse lines lacking the various sub-regions of CTR by genome editing and compared the embryonic lethality of homozygotes, and protein and mRNA expression levels of TDP-43. We demonstrated the functional diversity of the four segments of CTR, finding that the presence of the Q/N-rich segment greatly restored the protein stability of TDP-43. In addition, we found that the second GaroS deletion did not affect protein stability and mouse development.

DOI： 10.1038/s41598-022-19153-0

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失語症を来した小脳出血の1例

畠山公大, 大槻美佳, 木下悠紀子, 小出伸, 畠山祐樹, 佐治越爾, 金澤雅人, 小野寺理

日本神経心理学会総会プログラム・予稿集 46回 69 - 69 2022年8月

Clinical correlations of cerebrospinal fluid biomarkers including neuron-glia 2 and neurofilament light chain in patients with multiple system atrophy. 国際誌

Takayoshi Tokutake, Kensaku Kasuga, Tamao Tsukie, Takanobu Ishiguro, Takayoshi Shimohata, Osamu Onodera, Takeshi Ikeuchi

Parkinsonism & related disorders 102 30 - 35 2022年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Multiple system atrophy (MSA) is a progressive neurodegenerative disorder. The usefulness of biomarkers in diagnosing MSA has been recently reported, but few studies have investigated the correlations among cerebrospinal fluid (CSF) biomarkers or the relationship between CSF biomarkers and the clinical parameters of patients with MSA. Thus, this was the aim of our study. METHODS: We performed cross-sectional study of CSF biomarkers in 50 patients with MSA and 20 control subjects. Ten of the patients with MSA were longitudinally followed for a period of 2 ± 1 years (mean ± standard deviation) as a substudy. We quantified CSF biomarkers including α-synuclein (α-syn), β-amyloid42 (Aβ42), total tau (t-tau) and phosphorylated tau (p-tau), neurofilament light chain (NfL), and neuron-glia2 (NG2), and assessed their relationship with clinical parameters (clinical subtypes, motor symptoms, nonmotor symptoms, and disease progression). RESULTS: The levels of CSF α-syn, Aβ42, and p-tau were significantly lower, while those of NfL were higher in the patients with MSA than in the control subjects. Importantly, we found the significant elevation of soluble NG2 in the CSF of patients with MSA. CSF NfL showed the optimal diagnostic performance for MSA with levels at baseline significantly associated with longitudinal motor progression. With the exception of t-tau, there were no differences in the levels of CSF biomarkers between the MSA-parkinsonism and MSA-cerebellar subtypes. CONCLUSIONS: Our results suggest CSF levels of NG2 and NfL as possible diagnostic and prognostic biomarkers in MSA. Further study is necessary to validate these findings.

DOI： 10.1016/j.parkreldis.2022.07.007

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Stroke incidence and chronic kidney disease: A hospital-based prospective cohort study. 国際誌

Minako Wakasugi, Akio Yokoseki, Masakazu Wada, Kazuhiro Sanpei, Takeshi Momotsu, Kenji Sato, Hiroyuki Kawashima, Kazutoshi Nakamura, Osamu Onodera, Ichiei Narita

Nephrology (Carlton, Vic.) 27 ( 7 ) 577 - 587 2022年7月

Improving the Accuracy of Diagnosis for Multiple-System Atrophy Using Deep Learning-Based Method 査読国際誌

Yasuhiro Kanatani, Yoko Sato, Shota Nemoto, Manabu Ichikawa, Osamu Onodera

Biology 11 ( 7 ) 951 - 951 2022年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：{MDPI} {AG}

Multiple-system atrophy (MSA) is primarily an autonomic disorder with parkinsonism or cerebellar ataxia. Clinical diagnosis of MSA at an early stage is challenging because the symptoms change over the course of the disease. Recently, various artificial intelligence-based programs have been developed to improve the diagnostic accuracy of neurodegenerative diseases, but most are limited to the evaluation of diagnostic imaging. In this study, we examined the validity of diagnosis of MSA using a pointwise linear model (deep learning-based method). The goal of the study was to identify features associated with disease differentiation that were found to be important in deep learning. A total of 3377 registered MSA cases from FY2004 to FY2008 were used to train the model. The diagnostic probabilities of SND (striatonigral degeneration), SDS (Shy-Drager syndrome), and OPCA (olivopontocerebellar atrophy) were estimated to be 0.852 ± 0.107, 0.650 ± 0.235, and 0.858 ± 0.270, respectively. In the pointwise linear model used to identify and visualize features involved in individual subtypes, autonomic dysfunction was found to be a more prominent component of SDS compared to SND and OPCA. Similarly, respiratory failure was identified as a characteristic of SDS, dysphagia was identified as a characteristic of SND, and brain-stem atrophy was identified as a characteristic of OPCA.

DOI： 10.3390/biology11070951

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Efficacy and Safety of Ultrahigh-Dose Methylcobalamin in Early-Stage Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial. 国際誌

Ryosuke Oki, Yuishin Izumi, Koji Fujita, Ryosuke Miyamoto, Hiroyuki Nodera, Yasutaka Sato, Satoshi Sakaguchi, Hiroshi Nokihara, Kazuaki Kanai, Taiji Tsunemi, Nobutaka Hattori, Yuki Hatanaka, Masahiro Sonoo, Naoki Atsuta, Gen Sobue, Toshio Shimizu, Kazumoto Shibuya, Ken Ikeda, Osamu Kano, Kazuto Nishinaka, Yasuhiro Kojima, Masaya Oda, Kiyonobu Komai, Hitoshi Kikuchi, Nobuo Kohara, Makoto Urushitani, Yoshiaki Nakayama, Hidefumi Ito, Makiko Nagai, Kazutoshi Nishiyama, Daisuke Kuzume, Shun Shimohama, Takayoshi Shimohata, Koji Abe, Tomohiko Ishihara, Osamu Onodera, Sagiri Isose, Nobuyuki Araki, Mitsuya Morita, Kazuyuki Noda, Tatsushi Toda, Hirofumi Maruyama, Hirokazu Furuya, Satoshi Teramukai, Tatsuo Kagimura, Kensuke Noma, Hiroaki Yanagawa, Satoshi Kuwabara, Ryuji Kaji

JAMA neurology 79 ( 6 ) 575 - 583 2022年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Importance: The effectiveness of currently approved drugs for amyotrophic lateral sclerosis (ALS) is restricted; there is a need to develop further treatments. Initial studies have shown ultrahigh-dose methylcobalamin to be a promising agent. Objective: To validate the efficacy and safety of ultrahigh-dose methylcobalamin for patients with ALS enrolled within 1 year of onset. Design, Setting, and Participants: This was a multicenter, placebo-controlled, double-blind, randomized phase 3 clinical trial with a 12-week observation and 16-week randomized period, conducted from October 17, 2017, to September 30, 2019. Patients were recruited from 25 neurology centers in Japan; those with ALS diagnosed within 1 year of onset by the updated Awaji criteria were initially enrolled. Of those, patients fulfilling the following criteria after 12-week observation were eligible for randomization: 1- or 2-point decrease in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) total score, a percent forced vital capacity greater than 60%, no history of noninvasive respiratory support and tracheostomy, and being ambulatory. The target participant number was 64 in both the methylcobalamin and placebo groups. Patients were randomly assigned through an electronic web-response system to methylcobalamin or placebo. Interventions: Intramuscular injection of methylcobalamin (50-mg dose) or placebo twice weekly for 16 weeks. Main Outcomes and Measures: The primary end point was change in ALSFRS-R total score from baseline to week 16 in the full analysis set. Results: A total of 130 patients (mean [SD] age, 61.0 [11.7] years; 74 men [56.9%]) were randomly assigned to methylcobalamin or placebo (65 each). A total of 129 patients were eligible for the full analysis set, and 126 completed the double-blind stage. Of these, 124 patients proceeded to the open-label extended period. The least square means difference in ALSFRS-R total score at week 16 of the randomized period was 1.97 points greater with methylcobalamin than placebo (-2.66 vs -4.63; 95% CI, 0.44-3.50; P = .01). The incidence of adverse events was similar between the 2 groups. Conclusions and Relevance: Results of this randomized clinical trial showed that ultrahigh-dose methylcobalamin was efficacious in slowing functional decline in patients with early-stage ALS and with moderate progression rate and was safe to use during the 16-week treatment period. Trial Registration: ClinicalTrials.gov Identifier: NCT03548311.

DOI： 10.1001/jamaneurol.2022.0901

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全身性疾患に伴う脊椎病変頸椎除圧術後の上肢型筋萎縮側索硬化症の臨床経過

五十嵐哲也, 渡辺慶, 大橋正幸, 川島寛之, 三瓶一弘, 五十嵐修一, 黒羽泰子, 小池亮子, 石原智彦, 大津裕, 小野寺理

東北整形災害外科学会雑誌 65 ( 1 ) 167 - 168 2022年6月

Paving the Way Toward Meaningful Trials in Ataxias: An Ataxia Global Initiative Perspective. 国際誌

Thomas Klockgether, Tetsuo Ashizawa, Bernard Brais, Rosalind Chuang, Alexandra Durr, Brent Fogel, Julie Greenfield, Sue Hagen, Laura Bannach Jardim, Hong Jiang, Osamu Onodera, José Luiz Pedroso, Bin-Weng Soong, David Szmulewicz, Holm Graessner, Matthis Synofzik

Movement disorders : official journal of the Movement Disorder Society 37 ( 6 ) 1125 - 1130 2022年6月

臨床医のための神経病理再入門 CARASIL

齋藤理恵, 小野寺理, 柿田明美

Clinical Neuroscience 40 ( 6 ) 700 - 702 2022年6月

脳神経疾患克服に向けた研究推進の提言2020、各論(方法論別)

望月秀樹, 青木正志, 池中建介, 井上治久, 岩坪威, 宇川義一, 岡澤均, 小野賢二郎, 小野寺理, 北川一夫, 齊藤祐子, 下畑享良, 高橋良輔, 戸田達史, 中原仁, 松本理器, 水澤英洋, 三井純, 村山繁雄, 勝野雅央, 日本神経学会将来構想委員会

臨床神経学 62 ( 6 ) 429 - 442 2022年6月

脳神経疾患克服に向けた研究推進の提言2020、各論(疾患群別)

臨床神経学 62 ( 6 ) 443 - 457 2022年6月

Mortality factors in recurrent parathyroid cancer: a pooled analysis reply

Minako Wakasugi, Akio Yokoseki, Masakazu Wada, Takeshi Momotsu, Kenji Sato, Hiroyuki Kawashima, Kazutoshi Nakamura, Osamu Onodera, Ichiei Narita

JOURNAL OF BONE AND MINERAL METABOLISM 40 ( 3 ) 537 - 538 2022年5月

脳神経疾患克服に向けた研究推進の提言2020，各論I（方法論別）

望月秀樹, 青木正志, 池中建介, 井上治久, 岩坪威, 宇川義一, 岡澤均, 小野賢二郎, 小野寺理, 北川一夫, 齊藤祐子, 下畑享良, 髙橋良輔, 戸田達史, 中原仁, 松本理器, 水澤英洋, 三井純, 村山繁雄, 勝野雅央, 日本神経学会将来構想委員会, 青木吉嗣, 石浦浩之, 和泉唯信, 小池春樹, 島田斉, 髙橋祐二, 徳田隆彦, 中嶋秀人, 波田野琢, 三澤園子, 渡辺宏久

臨床神経学 advpub ( 6 ) 429 - 442 2022年5月

脳神経疾患克服に向けた研究推進の提言2020，各論II（疾患群別）

臨床神経学 advpub ( 6 ) 443 - 457 2022年5月

[ATTRv amyloidosis with early improvement demonstrated by the 6-minute walk test following Patisiran therapy: a case report].

Shinya Oginezawa, Tomohiko Ishihara, Yohei Iwafuchi, Yuya Hatano, Ken Kashimura, Osamu Onodera

Rinsho shinkeigaku = Clinical neurology 62 ( 5 ) 375 - 379 2022年4月

記述言語：日本語掲載種別：研究論文（学術雑誌）

We report the case of a 65-year-old man who gradually developed numbness in both hands, lower limb muscle weakness and atrophy, and orthostatic hypotension over two and a half years. These symptoms indicated hereditary ATTR amyloidosis (ATTRv amyloidosis), and the final diagnosis was established through proof of TTR gene mutation (V30M). We initiated patisiran therapy, and a continuous 6-minute walking test performed 3 weeks from the start of therapy demonstrated improvement in the walking distance. This is a single case report showing the improvement in the motor and sensory function on administration of patisiran monotherapy from an early stage.

DOI： 10.5692/clinicalneurol.cn-001693

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禿頭と腰椎症を呈し、ヘテロ接合性HTRA1変異を伴った脳小血管病の31歳女性例

安田真人, 杉山淳比古, 森雅裕, 水地智基, 福武敏夫, 上村昌寛, 小野寺理, 桑原聡

臨床神経学 62 ( 4 ) 314 - 314 2022年4月

Brain TDP-43 pathology in corticobasal degeneration: Topographical correlation with neuronal loss. 国際誌

Makoto Sainouchi, Mari Tada, Yusran Ady Fitrah, Norikazu Hara, Kou Tanaka, Jiro Idezuka, Izumi Aida, Takashi Nakajima, Akinori Miyashita, Kohei Akazawa, Takeshi Ikeuchi, Osamu Onodera, Akiyoshi Kakita

Neuropathology and applied neurobiology 48 ( 3 ) e12786 2022年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

AIMS: Neuronal and glial inclusions comprising transactive response DNA-binding protein of 43 kDa (TDP-43) have been identified in the brains of patients with corticobasal degeneration (CBD), and a possible correlation between the presence of these inclusions and clinical phenotypes has been speculated. However, the significance of TDP-43 pathology in the pathomechanism of CBD has remained unclear. Here, we investigated the topographical relationship between TDP-43 inclusions and neuronal loss in CBD. METHODS: We estimated semi-quantitatively neuronal loss and TDP-43 pathology in the form of neuronal cytoplasmic inclusions (NCIs), astrocytic inclusions (AIs), oligodendroglial cytoplasmic inclusions (GCIs), and dystrophic neurites in 22 CNS regions in 10 patients with CBD. Then, the degree of correlation between the severity of neuronal loss and the quantity of each type of TDP-43 inclusion was assessed. We also investigated tau pathology in a similar manner. RESULTS: TDP-43 pathology was evident in nine patients. The putamen and globus pallidus were the regions most frequently affected (80%). NCIs were the most prominent form, and their quantity was significantly correlated with the severity of neuronal loss in more than half of the regions examined. The quantities of TDP-43 NCIs and tau NCIs were correlated in only a few regions. The number of regions where the quantities of TDP-43 AIs and GCIs were correlated with the severity of neuronal loss was apparently small in comparison with that of NCIs. CONCLUSIONS: TDP-43 alterations in neurons, not closely associated with tau pathology, may be involved in the pathomechanism underlying neuronal loss in CBD. There was a significant topographical correlation between neuronal cytoplasmic aggregation of TDP-43 and neuronal loss in CBD, suggesting that TDP-43 protein aberration might be associated with neuronal degeneration in CBD. There was no close correlation between the burden of TDP-43 and that of tau in neurons.

DOI： 10.1111/nan.12786

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Authors' reply.

Minako Wakasugi, Akio Yokoseki, Masakazu Wada, Takeshi Momotsu, Kenji Sato, Hiroyuki Kawashima, Kazutoshi Nakamura, Osamu Onodera, Ichiei Narita

Journal of bone and mineral metabolism 40 ( 3 ) 537 - 538 2022年2月

Endogenous human retrovirus-K is not increased in the affected tissues of Japanese ALS patients. 国際誌

Tomohiko Ishihara, Akihide Koyama, Yuya Hatano, Ryoko Takeuchi, Yuka Koike, Taisuke Kato, Mari Tada, Akiyoshi Kakita, Osamu Onodera

Neuroscience research 178 78 - 82 2022年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

Activation of human endogenous retrovirus-K (HERV-K) is one of the proposed risk factors for amyotrophic lateral sclerosis (ALS). The HERV-K envelope protein has been reported to show neurotoxicity, and development of therapy with reverse transcriptase inhibitors is being investigated. On the other hand, some reports have failed to show HERV-K activation in ALS. In this study, we analyzed the expression of HERV-K mRNA in the motor cortex and spinal cord of 15 Japanese patients with sporadic ALS and 19 controls using reverse transcriptase droplet digital PCR. This revealed no significant increase of HERV-K expression in ALS-affected tissues, suggesting that the association between ALS and HERV-K remains questionable.

DOI： 10.1016/j.neures.2022.01.009

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Stem cell transplantation for pediatric patients with adrenoleukodystrophy: A nationwide retrospective analysis in Japan. 国際誌

Koji Kato, Hiromasa Yabe, Nobuyuki Shimozawa, Souichi Adachi, Mineo Kurokawa, Yoshiko Hashii, Atsushi Sato, Nao Yoshida, Makiko Kaga, Osamu Onodera, Shunichi Kato, Yoshiko Atsuta, Tomohiro Morio

Pediatric transplantation 26 ( 1 ) e14125 2022年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Adrenoleukodystrophy (ALD) is an X-linked recessive disorder and 30-40% of patients develop progressive cerebral neurodegeneration. For symptomatic ALD patients, allogeneic stem cell transplantation (SCT) is considered the standard treatment modality to stabilize or prevent the progression of neurological symptoms. METHODS: We retrospectively analyzed the transplant outcomes of 99 pediatric patients with cerebral ALD in Japan. The conditioning regimens included Regimen A: fludarabine/melphalan/low-dose total body irradiation (TBI) with brain sparing (n = 39), Regimen B; busulfan/cyclophosphamide ± others (n = 23), Regimen C: melphalan/total lymphoid irradiation/thoracoabdominal irradiation ± anti-T lymphocyte globulin ± fludarabine (n = 27), and Regimen D: others (n = 10). RESULTS: The 5-year overall survival (OS) and event-free survival (EFS) of all patients were 90.0% and 72.9%, respectively. The 5-year OS was 100.0% for Regimen A, 91.1% for Regimen B, 84.4% for Regimen C, and 67.5% for Regimen D (p = 0.028). The 5-year EFS was 78.3% for Regimen A, 78.0% for Regimen B, 70.4% for Regimen C, and 48.0% for Regimen D (p = 0.304). The OS marginally improved after 2007 compared with before 2006 (95.3% vs. 85.2%, p = 0.066), due to the improvement of cord blood transplantation (CBT) outcomes after 2007 compared with before 2006 (96.6% vs. 68.4%, p = 0.005). On magnetic resonance imaging of the brain, a reduced Loes score after SCT was only observed in one of the 15 bone marrow transplantation (BMT) patients, but in 5 of the 15 CBT patients (p = 0.173). CONCLUSIONS: Our study revealed that a reduced conditioning regimen with fludarabine/melphalan/low-dose TBI provides better outcomes, and the results of CBT significantly improved after 2007.

DOI： 10.1111/petr.14125

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USP10 inhibits aberrant cytoplasmic aggregation of TDP-43 by promoting stress granule clearance. 国際誌

Masahiko Takahashi, Hiroki Kitaura, Akiyoshi Kakita, Taichi Kakihana, Yoshinori Katsuragi, Osamu Onodera, Yuriko Iwakura, Hiroyuki Nawa, Masaaki Komatsu, Masahiro Fujii

Molecular and cellular biology 42 ( 3 ) MCB0039321 2022年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

TDP-43 is a causative factor of amyotrophic lateral sclerosis (ALS). Cytoplasmic TDP-43 aggregates in neurons are a hallmark pathology of ALS. Under various stress conditions, TDP-43 localizes sequentially to two cytoplasmic protein aggregates: stress granules (SGs) first, and then aggresomes. Accumulating evidence suggests that delayed clearance of TDP-43-positive SGs is associated with pathological TDP-43 aggregates in ALS. We found that USP10 promotes the clearance of TDP-43-positive SGs in cells treated with proteasome inhibitor, thereby promoting the formation of TDP-43-positive aggresomes, and the depletion of USP10 increases the amount of insoluble TDP-35, a cleaved product of TDP-43, in the cytoplasm. TDP-35 interacted with USP10 in an RNA-binding dependent manner; however, impaired RNA-binding of TDP-35 reduced the localization in SGs and aggresomes and induced USP10-negative TDP-35 aggregates. Immunohistochemistry showed that most of the cytoplasmic TDP-43/TDP-35-aggregates in the neurons of ALS patients were USP10-negative. Our findings suggest that USP10 inhibits aberrant aggregation of TDP-43/TDP-35 in the cytoplasm of neuronal cells by promoting the clearance of TDP-43/TDP-35-positive SGs and facilitating the formation of TDP-43/TDP-35-positive aggresomes.

DOI： 10.1128/MCB.00393-21

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Polypharmacy, chronic kidney disease, and incident fragility fracture: a prospective cohort study.

Minako Wakasugi, Akio Yokoseki, Masakazu Wada, Takeshi Momotsu, Kenji Sato, Hiroyuki Kawashima, Kazutoshi Nakamura, Osamu Onodera, Ichiei Narita

Journal of bone and mineral metabolism 40 ( 1 ) 157 - 166 2022年1月

Imaging Characteristics for Predicting Cognitive Impairment in Patients With Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy. 国際誌

Akira Taniguchi, Akihiro Shindo, Ken-Ichi Tabei, Osamu Onodera, Yukio Ando, Takao Urabe, Kazumi Kimura, Kazuo Kitagawa, Yoshihiro Miyamoto, Misa Takegami, Masafumi Ihara, Ikuko Mizuta, Toshiki Mizuno, Hidekazu Tomimoto

Frontiers in aging neuroscience 14 876437 - 876437 2022年

記述言語：英語掲載種別：研究論文（学術雑誌）

Objectives: Patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) show various clinical symptoms, including migraine, recurrent stroke, and cognitive impairment. We investigated the associations between magnetic resonance imaging (MRI) markers of small vessel disease and neuropsychological tests and identified the MRI characteristics for predicting cognitive impairment in patients with CADASIL. Methods: Subjects included 60 CADASIL patients diagnosed with genetic tests and registered in the Japanese CADASIL REDCap database between June 2016 and December 2020. Patient information including clinical data, modified Rankin Scale (mRS); MRI findings of small vessel disease including periventricular and deep white matter lesions (WML), lacunar infarcts, and cerebral microbleeds (CMBs); and neuropsychological tests, including the Japanese version of the Mini-Mental State Examination (MMSE), the Japanese version of the Montreal Cognitive Assessment (MoCA-J), and the Frontal Assessment Battery (FAB), were evaluated. Results: Data from 44 CADASIL patients were eligible for this study, compared between patients with and without dementia. Regarding the neuroimaging findings, the Fazekas score of periventricular and deep WML was higher in patients with dementia (periventricular, p = 0.003; deep, p = 0.009). The number of lacunar infarcts was higher in patients with dementia (p = 0.001). The standardized partial regression coefficient (SPRC) in MoCA-J was 0.826 (95% CI, 0.723-0.942; p = 0.005) for the number of CMBs. The SPRC in MMSE was 0.826 (95% CI, 0.719-0.949; p = 0.007) for the number of CMBs. The SPRC for FAB decreased significantly to 0.728 (95% CI, 0.551-0.960; p = 0.024) for the number of lacunar infarcts. Receiver operating characteristic (ROC) curves for dementia showed that in the number of lacunar infarcts, a cut-off score of 5.5 showed 90.9% sensitivity and 61.1% specificity. For the number of CMBs, a cut-off score of 18.5 showed 45.5% sensitivity and 100% specificity. Conclusion: The characteristic MRI findings were that CADASIL patients with dementia had severe WML, both periventricular and deep, and a larger number of lacunar infarcts than those without dementia. The risk of dementia may be associated with ≥ 6 lacunar infarcts, ≥19 CMBs, or a Fazekas scale score of 3 in periventricular and deep WML.

DOI： 10.3389/fnagi.2022.876437

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Neuronal Intranuclear Inclusion Disease Presenting with Voice Tremor 国際誌

Tomone Taneda, Masato Kanazawa, Yo Higuchi, Hironori Baba, Aiko Isami, Masahiro Uemura, Takuya Konno, Arata Horii, Takeshi Ikeuchi, Osamu Onodera

Movement Disorders Clinical Practice 9 ( 3 ) 404 - 406 2021年12月

Parkinson's disease and parkinsonism: Clinicopathological discrepancies on diagnosis in three patients. 国際誌

Yasuko Toyoshima, Hitoshi Takahashi, Shinnichi Katada, Naoyuki Kojima, Mari Tada, Takashi Tani, Ryoko Koike, Takanori Nozawa, Izumi Aida, Takashi Nakajima, Osamu Onodera, Akiyoshi Kakita

Neuropathology : official journal of the Japanese Society of Neuropathology 41 ( 6 ) 450 - 456 2021年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

Parkinson's disease (PD) is one of the most common neurodegenerative disorders. The cardinal neuropathological features of PD include selective and progressive loss of pigmented neurons in the substantia nigra, deficiencies in dopaminergic signaling in the striatum, and occurrence of phosphorylated α-synuclein-identified Lewy bodies in the nervous system. Parkinsonism, the clinical presentation of movement disorders seen in PD, is a feature shared commonly by other pathologically distinct neurodegenerative diseases, such as progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and multiple system atrophy (MSA). Consequently, it is sometimes difficult to distinguish PD from such parkinsonism-related neurological disorders. In addition, parkinsonism is not always a feature of certain neurodegenerative diseases, and it can sometimes develop as a result of various forms of drug intoxication or cerebrovascular disease. Here, we describe the clinicopathological features of three patients (cases 1, 2, and 3) diagnosed as having PSP, MSA, and PD, respectively, in each of whom the postmortem histopathological diagnosis differed from the final clinical diagnosis. Neuropathologically, they had suffered from coexistent disorders: PD, MSA, and argyrophilic grain disease (case 1); PD (case 2); and vascular parkinsonism (case 3). The variety of patients showing features of parkinsonism underlines the importance of careful long-term follow up followed by postmortem neuropathological evaluation.

DOI： 10.1111/neup.12777

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[Recommendations (Proposal) for promoting research for overcoming neurological diseases 2020].

Hideki Mochizuki, Masashi Aoki, Kensuke Ikenaka, Haruhisa Inoue, Takeshi Iwatsubo, Yoshikazu Ugawa, Hitoshi Okazawa, Kenjiro Ono, Osamu Onodera, Kazuo Kitagawa, Yuko Saito, Takayoshi Shimohata, Ryosuke Takahashi, Tatsushi Toda, Jin Nakahara, Riki Matsumoto, Hidehiro Mizusawa, Jun Mitsui, Shigeo Murayama, Masahisa Katsuno, Yoshitsugu Aoki, Hiroyuki Ishiura, Yuishin Izumi, Haruki Koike, Hitoshi Shimada, Yuji Takahashi, Takahiko Tokuda, Hideto Nakajima, Taku Hatano, Sonoko Misawa, Hirohisa Watanabe

Rinsho shinkeigaku = Clinical neurology 61 ( 11 ) 709 - 721 2021年11月

記述言語：日本語掲載種別：研究論文（学術雑誌）

The Japanese Society of Neurology discusses research, education, and medical care in the field of neurology and makes recommendations to the national government. Dr. Mizusawa, the former representative director of the Japanese Society of Neurology, selected committee members and made "Recommendations for Promotion of Research for Overcoming Neurological Diseases" in 2013. After that, the Future Vision Committee was established in 2014, and these recommendations have been revised once every few years by the committee. This time, the Future Vision Committee made the latest recommendations from 2020 to 2021. In this document, the general part is 1) What is neurological disease? 2) Current status of neurological disease overcoming research, 3) Significance and necessity of neurological disease overcoming research, 4) Research promotion system for overcoming neurological disease, 5) the roadmap for overcoming neuromuscular diseases, 6) a summary version of these recommendations are explained using figures that are easy for the general public to understand.

DOI： 10.5692/clinicalneurol.cn-001639

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ラット脳虚血後のリン酸化タウ発現の経時変化

大津裕, 金山武史, 二宮格, 畠山公大, 小野寺理, 金澤雅人

脳循環代謝 33 ( 1 ) 96 - 96 2021年11月

加齢と関連したDNA脱メチル化がTDP-43量の自己調節機構を障害する

小池佑佳, 須貝章弘, 原範和, 伊藤絢子, 横関明男, 石原智彦, 山岸拓磨, 坪口晋太朗, 他田真理, 池内健, 柿田明美, 小野寺理

Dementia Japan 35 ( 4 ) 610 - 610 2021年10月

パチシラン単独投与で早期より運動機能が改善したATTRアミロイドーシスの1例

荻根沢真也, 石原智彦, 岩淵洋平, 畠野雄也, 柏村健, 小野寺理

神経治療学 38 ( 6 ) S293 - S293 2021年10月

神経核内封入体病(NIID)におけるNOTCH2NLCリピート伸長と臨床的特徴の検討

樋口陽, 原範和, Yusran Ady Fitrah, 種田朝音, 徳武孝允, 三浦健, 岩淵洋平, 五十嵐修一, 林秀樹, 石黒敬信, 三瓶一弘, 武田勇人, 高橋俊昭, 金澤雅人, 宮下哲典, 小野寺理, 池内健

Dementia Japan 35 ( 4 ) 612 - 612 2021年10月

Do patients with multiple system atrophy have decreased nocturnal urinary concentration? 国際誌

Yusuke Sakata, Masato Kanazawa, Masahiro Hatakeyama, Takuya Konno, Tetsutaro Ozawa, Osamu Onodera

Clinical autonomic research : official journal of the Clinical Autonomic Research Society 2021年9月

小字症を呈した自己免疫性脳幹脳炎の臨床的特徴

助川真響, 畠山公大, 羽入龍太郎, 滑川将気, 大津裕, 橋田裕美, 金澤雅人, 小野寺理

臨床神経学 61 ( Suppl. ) S431 - S431 2021年9月

Hemiplegic-type ALS: clinicopathological features of two autopsied patients. 国際誌

Makoto Sainouchi, Hidetomo Tanaka, Hiroshi Shimizu, Takuya Mashima, Takao Fukushima, Yuya Hatano, Tomohiko Ishihara, Kunihiko Makino, Osamu Onodera, Akiyoshi Kakita

Journal of neurology, neurosurgery, and psychiatry 92 ( 9 ) 1014 - 1016 2021年9月

[Rethinking Lacunar Stroke: Beyond Fisher's Curse].

Osamu Onodera, Masahiro Uemura, Shoichiro Ando, Hideki Hayashi, Masato Kanazawa

Brain and nerve = Shinkei kenkyu no shinpo 73 ( 9 ) 991 - 998 2021年9月

記述言語：日本語掲載種別：研究論文（学術雑誌）

Lipohyalinosis is an important concept in the independence of lacunar stroke; however, its role has been overemphasized and has led to much confusion in the understanding of lacunar stroke. Classical lipohyalinosis has declined following the widespread availability of antihypertensive therapy, and lacunar stroke secondary to age-related hyaline atherosclerosis is more commonly observed in clinical practice. Clinically diagnosed lacunar stroke is associated with several etiopathogenetic contributors. Excluding cardiogenic embolism, lacunar stroke can be categorized based on the detection of an atheroma. Atheroma imaging is possible in recent years, and strokes that are not associated with an atheroma are shown to present with deep white matter hyperintensity on MRI. Additionally, risk gene analysis has confirmed a group of risk genes associated with the extracellular matrix in lacunar stroke with white matter hyperintensity on MRI. These findings suggest the role of a variety of etiopathogenetic mechanisms underlying lacunar stroke and that lacunar stroke with deep white matter hyperintensity on MRI may be attributable to unique pathogenetic contributors. This group is known to be strongly associated with genetic contributors. Hopefully, lacunar stroke will be diagnosed from this perspective with the development of interventional strategies tailored to the pathogenesis of this condition.

DOI： 10.11477/mf.1416201876

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Visual outcome of aquaporin-4 antibody-positive optic neuritis with maintenance therapy.

Satoshi Ueki, Tetsuhisa Hatase, Megumi Kiyokawa, Izumi Kawachi, Etsuji Saji, Osamu Onodera, Takeo Fukuchi, Hironaka Igarashi

Japanese journal of ophthalmology 65 ( 5 ) 699 - 703 2021年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

PURPOSE: To assess the effect of maintenance therapy on visual outcomes in preventing recurrences one year after first onset in patients with aquaporin-4 antibody (AQP4Ab)-positive optic neuritis. STUDY DESIGN: Retrospective study. METHODS: The medical charts of 56 patients with optic neuritis (22 with AQP4Ab-positive and 34 with AQP4Ab-negative) at Niigata University Medical and Dental Hospital were retrospectively analyzed. Clinical characteristics, including visual acuity and number of recurrences one year after first onset, were compared among patients who were AQP4Ab-positivie with and those without maintenance therapy such as oral prednisolone and azathioprine, as well as those who were AQP4Ab-negative. RESULTS: The mean ages were 49.3 and 45.2 years in the AQP4Ab-positive and the AQP4Ab-negative groups. The female to male ratio was 21:1 and 18:16 in the two groups, respectively. Multiple between-group comparison showed a statistically significant difference in visual acuity one year after first onset between the AQP4Ab-positive without maintenance therapy group and the AQP4Ab-negative group (0.05 (median, same applies below) vs. 1.0, p < 0.01). There was also a statistically significant difference in the number of recurrences in the year after first onset between the AQP4Ab-positive with and without maintenance therapy groups (1 vs. 0, p < 0.01). CONCLUSION: This study demonstrates that patients with AQP4Ab-positive optic neuritis without maintenance therapy had the poorest visual acuity and the most recurrences one year after first onset. These results indicate that reducing the number of recurrences with maintenance therapy could improve the visual outcomes in patients with AQP4Ab-positive optic neuritis.

DOI： 10.1007/s10384-021-00858-0

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軟口蓋ミオクローヌスに対する下顎アプローチによる超音波検査

小出眞悟, 今野卓哉, 柏木健太, 柴田健太郎, 柳村文寛, 徳武孝允, 堅田慎一, 小野寺理

臨床神経学 61 ( Suppl. ) S341 - S341 2021年9月

[A case of subcortical hemorrhage due to infective endocarditis caused by Staphylococcus warneri without fever and leukocytosis].

Tomone Taneda, Takuya Konno, Ayaka Ono, Takayoshi Tokutake, Osamu Onodera

Rinsho shinkeigaku = Clinical neurology 61 ( 8 ) 563 - 566 2021年8月

記述言語：日本語掲載種別：研究論文（学術雑誌）

A 50-year-old man with mitral regurgitation presented with right frontal subcortical hemorrhage. Although he had no fever and his white blood cell count was in the normal range, CT angiography demonstrated a micro cerebral aneurysm, and all three blood cultures were positive for Staphylococcus warneri (S. warneri). Thus, we diagnosed him with infective endocarditis. His condition improved successfully by immediate antibiotics and cerebral aneurysm clipping. S. warneri is a member of coagulase-negative staphylococci that are low-virulence and resident flora of the skin. S. warneri rarely causes infective endocarditis on native valves. Infective endocarditis caused by S. warneri manifests insidious course without inflammatory reactions such as fever and leukocytosis, and thus, diagnosis can be delayed. Attention should be paid to a patient who develops subcortical hemorrhage without a history of hypertension or inflammatory reactions as in this case.

DOI： 10.5692/clinicalneurol.cn-001613

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Predictive markers based on transcriptome modules for vinorelbine-based adjuvant chemotherapy for lung adenocarcinoma patients. 国際誌

Shoko Nakasone, Ayako Suzuki, Hitomi Okazaki, Keiichi Onodera, Junko Zenkoh, Genichiro Ishii, Yutaka Suzuki, Masahiro Tsuboi, Katsuya Tsuchihara

Lung cancer (Amsterdam, Netherlands) 158 115 - 125 2021年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVES: Microtubule inhibitors (MTIs) are widely used as anti-cancer drugs for various types of tumors. Vinorelbine, an MTI, is utilized in postoperative adjuvant chemotherapy, especially for lung adenocarcinoma. However, no molecular markers are able to identify patients for whom MTIs would be effective. In this study, we attempted to identify practical markers to predict the efficacy of MTI-based adjuvant chemotherapy. MATERIALS AND METHODS: We explored a novel combination of molecular marker candidates, based on gene expression network analysis constructed using an omics panel of 26 lung adenocarcinoma cell lines. We then applied the obtained classification method to predict the efficacy of MTI treatment in patients who received adjuvant chemotherapy. RNA sequencing (RNA-seq) analysis was conducted using surgical specimens from 24 Japanese lung adenocarcinoma patients treated postoperatively with vinorelbine. RESULTS: We identified four modules within the network with module activities that were significantly associated with sensitivity to MTIs. Two modules were associated with high sensitivity to MTIs: genes with low differentiation or transdifferentiation of lung adenocarcinomas. On the other hand, MTI-low sensitivity modules were enriched in common epithelial genes and markers of well-differentiated lung adenocarcinomas. We also classified lung adenocarcinoma cases using the module activities associated with MTI efficacy and stratify the cases with MTI resistance. CONCLUSION: We demonstrate that the constructed classification method is useful for identifying patients with MTI resistance which results in a high risk of cancer relapse.

DOI： 10.1016/j.lungcan.2021.06.011

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Immunological abnormalities in patients with early-onset ataxia with ocular motor apraxia and hypoalbuminemia. 国際誌

Tamaki Kato, Yoshiteru Tamura, Hiroshi Matsumoto, Osamu Kobayashi, Hideaki Ishiguro, Masaya Ogawa, Koyo Tsujikawa, Yasuhiro Hasegawa, Mitsuhiro Sakamoto, Masaaki Konagaya, Hideki Houzen, Masatoshi Takagi, Kohsuke Imai, Tomohiro Morio, Akio Yokoseki, Osamu Onodera, Shigeaki Nonoyama

Clinical immunology (Orlando, Fla.) 229 108776 - 108776 2021年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

Early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH) is a neurodegenerative disorder caused by mutation in the aprataxin (APTX)-coding gene APTX, which is involved in DNA single-strand break repair (SSBR). The neurological abnormalities associated with EAOH are similar to those observed in patients with ataxia-telangiectasia. However, the immunological abnormalities in patients with EAOH have not been described. In this study, we report that EAOH patients have immunological abnormalities, including lymphopenia; decreased levels of CD4+ T-cells, CD8+ T-cells, and B-cells; hypogammaglobulinemia; low T-cell recombination excision circles and kappa-deleting element recombination circles; and oligoclonality of T-cell receptor β-chain variable repertoire. These immunological abnormalities vary among the EAOH patients. Additionally, mild radiosensitivity in the lymphocytes obtained from the patients with EAOH was demonstrated. These findings suggested that the immunological abnormalities and mild radiosensitivity evident in patients with EAOH could be probably caused by the DNA repair defects.

DOI： 10.1016/j.clim.2021.108776

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Pyloric-gland metaplasia may be an origin of cancer and intestinal metaplasia with possible CDX2 expression. 国際誌

Kazuyoshi Yagi, Atsunori Tsuchiya, Satoru Hashimoto, Taisuke Kato, Osamu Onodera, Shuji Terai

Gastroenterology report 9 ( 4 ) 370 - 373 2021年8月

The optineurin/TIA1 pathway inhibits aberrant stress granule formation and reduces ubiquitinated TDP-43. 国際誌

Taichi Kakihana, Masahiko Takahashi, Yoshinori Katsuragi, Shun-Ichi Yamashita, Junya Sango, Tomotake Kanki, Osamu Onodera, Masahiro Fujii

iScience 24 ( 7 ) 102733 - 102733 2021年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron disease characterized by the formation of cytoplasmic ubiquitinated TDP-43 protein aggregates in motor neurons. Stress granules (SGs) are stress-induced cytoplasmic protein aggregates containing various neuropathogenic proteins, including TDP-43. Several studies have suggested that SGs are the initial site of the formation of pathogenic ubiquitinated TDP-43 aggregates in ALS neurons. Mutations in the optineurin (OPTN) and TIA1 genes are causative factors of familial ALS with TDP-43 aggregation pathology. We found that both OPTN depletion and ALS-associated OPTN mutations upregulated the TIA1 level in cells recovered from heat shock, and this upregulated TIA1 increased the amount of ubiquitinated TDP-43. Ubiquitinated TDP-43 induced by OPTN depletion was localized in SGs. Our study suggests that ALS-associated loss-of-function mutants of OPTN increase the amount of ubiquitinated TDP-43 in neurons by increasing the expression of TIA1, thereby promoting the aggregation of ubiquitinated TDP-43.

DOI： 10.1016/j.isci.2021.102733

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Correction to: A novel splicing variant of ANXA11 in a patient with amyotrophic lateral sclerosis: histologic and biochemical features. 国際誌

Makoto Sainouchi, Yuya Hatano, Mari Tada, Tomohiko Ishihara, Shoichiro Ando, Taisuke Kato, Jun Tokunaga, Gaku Ito, Hiroaki Miyahara, Yasuko Toyoshima, Akio Yokoseki, Tetsutaro Ozawa, Kohei Akazawa, Osamu Onodera, Akiyoshi Kakita

Acta neuropathologica communications 9 ( 1 ) 115 - 115 2021年6月

A novel splicing variant of ANXA11 in a patient with amyotrophic lateral sclerosis: histologic and biochemical features. 国際誌

Acta neuropathologica communications 9 ( 1 ) 106 - 106 2021年6月

Selective Synthesis of Acylated Cross-Benzoins from Acylals and Aldehydes via N-Heterocyclic Carbene Catalysis. 国際誌

Kou Onodera, Ryo Takashima, Yumiko Suzuki

Organic letters 23 ( 11 ) 4197 - 4202 2021年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

The utility of acylals as building blocks for selective cross-benzoin synthesis was explored in this study. The synthesis of α-acetoxyketones (O-acyl cross-benzoins) was achieved via selective N-heterocyclic carbene-catalyzed cross-benzoin reactions using acylals as aldehyde equivalents. Thus, the combination of ortho-substituted phenyl acylals and aromatic/aliphatic aldehydes as coupling substrates using bicyclic triazolium salts as precatalysts and potassium carbonate as a base in THF at reflux temperature selectively yielded O-acyl cross-benzoins.

DOI： 10.1021/acs.orglett.1c01134

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Cytosolic dsDNA of mitochondrial origin induces cytotoxicity and neurodegeneration in cellular and zebrafish models of Parkinson's disease. 国際誌

Hideaki Matsui, Junko Ito, Noriko Matsui, Tamayo Uechi, Osamu Onodera, Akiyoshi Kakita

Nature communications 12 ( 1 ) 3101 - 3101 2021年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

Mitochondrial dysfunction and lysosomal dysfunction have been implicated in Parkinson's disease (PD), but the links between these dysfunctions in PD pathogenesis are still largely unknown. Here we report that cytosolic dsDNA of mitochondrial origin escaping from lysosomal degradation was shown to induce cytotoxicity in cultured cells and PD phenotypes in vivo. The depletion of PINK1, GBA and/or ATP13A2 causes increases in cytosolic dsDNA of mitochondrial origin and induces type I interferon (IFN) responses and cell death in cultured cell lines. These phenotypes are rescued by the overexpression of DNase II, a lysosomal DNase that degrades discarded mitochondrial DNA, or the depletion of IFI16, which acts as a sensor for cytosolic dsDNA of mitochondrial origin. Reducing the abundance of cytosolic dsDNA by overexpressing human DNase II ameliorates movement disorders and dopaminergic cell loss in gba mutant PD model zebrafish. Furthermore, IFI16 and cytosolic dsDNA puncta of mitochondrial origin accumulate in the brain of patients with PD. These results support a common causative role for the cytosolic leakage of mitochondrial DNA in PD pathogenesis.

DOI： 10.1038/s41467-021-23452-x

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Differences in the isotopic signature of activated sludge in four types of advanced treatment processes at a municipal wastewater treatment plant. 国際誌

Takashi Onodera, Kazuhiro Komatsu, Ayato Kohzu, Gen Kanaya, Motoyuki Mizuochi, Kazuaki Syutsubo

Journal of environmental management 286 112264 - 112264 2021年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

The natural abundance of stable isotopes is a powerful tool for evaluating biological reactions and process conditions. However, there are few stable isotope studies on the wastewater treatment process. This study carried out the first investigation on variations in natural abundance of carbon and nitrogen stable isotope ratios (δ13C and δ15N) of activated sludge in four types of advanced treatment process (extended aeration activated sludge (EAAS), aerobic-anoxic-aerobic (A2O), recycled nitrification-denitrification (RND), and modified Bardenpho (MB)) at a municipal wastewater treatment plant. The δ13C and δ15N values of influent suspended solids settled in the primary sedimentation tank (i.e., primary sludge) ranged from -25.4‰ to -24.6‰ and 0.5‰-2.9‰, respectively, during monitoring periods. The δ13C values of the activated sludge were -24.6‰ to -23.6‰ (EAAS), -25.4‰ to -24.3‰ (A2O), -25.7‰ to -24.9‰ (RND), and -25.7‰ to -24.3‰ (MB). The δ13C values of the activated sludge were similar to those of influent suspended solids. However, the δ13C values of activated sludge in EAAS was significantly higher than in A2O, RND, and MB. Meanwhile, the δ15N values of activated sludge were obviously higher than influent suspended solids; 5.8‰-7.5‰ (EAAS), 6.6‰-8.1‰ (A2O), 5.5‰-7.5‰ (RND), and 5.3‰-7.6‰ (MB). Changes in δ13C and δ15N values of the activated sludge within the treatment system were also found. These findings indicate that changes in δ13C and δ15N values of the activated sludge rely on important function for biological wastewater treatment such as nitrification, denitrification, and methane oxidation through wastewater treatment over time.

DOI： 10.1016/j.jenvman.2021.112264

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Evaluation of stable isotope ratios (δ15N and δ18O) of nitrate in advanced sewage treatment processes: Isotopic signature in four process types. 国際誌

Takashi Onodera, Kazuhiro Komatsu, Ayato Kohzu, Gen Kanaya, Motoyuki Mizuochi, Kazuaki Syutsubo

The Science of the total environment 762 144120 - 144120 2021年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

Stable isotope ratios of nitrate are a powerful tool to evaluate aquatic environment stress from treated and untreated sewage. However, there is generally a lack of knowledge on the change in stable isotope ratios within wastewater treatment plants. We investigated nitrogen and oxygen stable isotope ratios (δ15N and δ18O) of nitrate in four types of advanced treatment processes operated in parallel; (A) extended aeration activated sludge, (B) anaerobic-anoxic-aerobic (A2O), (C) recycled nitrification-denitrification, and (D) modified Bardenpho. The results exhibited spatial variation of δ15N and δ18O for nitrate within the treatment steps. The changes in δ15N and δ18O may result from the reactor conditions (aerobic, anoxic, and anaerobic) and the order of these processes. As decreasing nitrate concentration in the anoxic stages, the δ15N/δ18O ratio for nitrate increased at a rate of 1.3 to 1.6 coupling with the reduction in the nitrate concentration in the anoxic stages. The δ15N and δ18O signatures were attributed to process performance in regard to nitrogen removal. In particular, the modified Bardenpho process has higher nitrogen removal efficiency over other processes, producing effluent with lower nitrate concentration and higher stable isotopes (δ15N: 23.6 to 25.5‰, δ18O: 2.8 to 4.5‰). We concluded that the stable isotope signatures mirrored the treatment efficiency and effluent characteristics.

DOI： 10.1016/j.scitotenv.2020.144120

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Heterozygous Cysteine-sparing NOTCH3 Variant p.Val237Met in a Japanese Patient with Suspected Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy: A Case Report.

Yuya Kano, Ikuko Mizuta, Akihiko Ueda, Hiroaki Nozaki, Keita Sakurai, Osamu Onodera, Yukio Ando, Kentaro Yamada, Hiroyuki Yuasa, Toshiki Mizuno

Internal medicine (Tokyo, Japan) 60 ( 15 ) 2479 - 2482 2021年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

A 64-year-old Japanese man with recurrent cerebral ischemic events and cognitive impairment was suspected of having cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) because of a family history and brain magnetic resonance imaging findings of cerebral white matter hyperintensities. The cysteine-sparing variation p.Val237Met was identified in NOTCH3. An intensive skin biopsy showed negative results (no granular osmiophilic material or positive NOTCH3 immunostaining), suggesting that the patient's definite diagnosis and pathogenicity of p.Val237Met were uncertain. We additionally reviewed previous reports of two Japanese families with p.Val237Met.

DOI： 10.2169/internalmedicine.6096-20

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Progressive micrographia without parkinsonism caused by autoimmune brainstem encephalitis: A case report. 国際誌

Ryutaro Hanyu, Masahiro Hatakeyama, Masaki Namekawa, Yutaka Otsu, Mayura Sukegawa, Hiromi Hashida, Izumi Kawachi, Masato Kanazawa, Osamu Onodera

Clinical neurology and neurosurgery 202 106496 - 106496 2021年3月

頸椎除圧術後の上肢型筋萎縮索硬化症の臨床経過

五十嵐哲也, 渡辺慶, 大橋正幸, 川島寛之, 三瓶一弘, 五十嵐修一, 黒羽泰子, 小池亮子, 石原智彦, 大津裕, 小野寺理

日本整形外科学会雑誌 95 ( 2 ) S112 - S112 2021年3月

Genetic Variations and Neuropathologic Features of Patients With PRKN Mutations. 国際誌

Naohiko Seike, Akio Yokoseki, Ryoko Takeuchi, Kento Saito, Hiroaki Miyahara, Akinori Miyashita, Tetsuhiko Ikeda, Izumi Aida, Takashi Nakajima, Masato Kanazawa, Masatoshi Wakabayashi, Yasuko Toyoshima, Hitoshi Takahashi, Riki Matsumoto, Tatsushi Toda, Osamu Onodera, Atsushi Ishikawa, Takeshi Ikeuchi, Akiyoshi Kakita

Movement disorders : official journal of the Movement Disorder Society 36 ( 7 ) 1634 - 1643 2021年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Mutations in PRKN are the most common cause of autosomal recessive juvenile parkinsonism. The objective of this study was to investigate the association between genotype and pathology in patients with PRKN mutations. METHODS: We performed a sequence and copy number variation analysis of PRKN, mRNA transcripts, Parkin protein expression, and neuropathology in 8 autopsied patients. RESULTS: All the patients harbored biallelic PRKN mutations. Two patients were homozygous and heterozygous, respectively, for the missense mutation p.C431F. Seven patients had exon rearrangements, including 2 patients from a single family who harbored a homozygous deletion of exon 4, and 3 patients who carried a homozygous duplication of exons 6-7, a homozygous duplication of exons 10-11, and a heterozygous duplication of exons 2-4. In the other 2 patients, we found a compound heterozygous duplication of exon 2, deletion of exon 3, and a heterozygous duplication of exon 2. However, sequencing of cDNA prepared from mRNA revealed 2 different transcripts derived from triplication of exon 2 and deletion of exons 2-3 and from duplication of exons 2-4 and deletion of exons 3-4. Western blotting and immunohistochemistry revealed faint or no expression of Parkin in their brains. In the substantia nigra pars compacta, a subfield-specific pattern of neuronal loss and mild gliosis were evident. Lewy bodies were found in 3 patients. Peripheral sensory neuronopathy was a feature. CONCLUSIONS: Genomic and mRNA analysis is needed to identify the PRKN mutations. Variable mutations may result in no or little production of mature Parkin and the histopathologic features may be similar.

DOI： 10.1002/mds.28521

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Corrigendum: HTRA1 Mutations Identified in Symptomatic Carriers Have the Property of Interfering the Trimer-Dependent Activation Cascade. 国際誌

Masahiro Uemura, Hiroaki Nozaki, Akihide Koyama, Naoko Sakai, Shoichiro Ando, Masato Kanazawa, Taisuke Kato, Osamu Onodera

Frontiers in neurology 12 756038 - 756038 2021年

Strategies to prevent hemorrhagic transformation after reperfusion therapies for acute ischemic stroke: A literature review. 国際誌

Yutaka Otsu, Masaki Namekawa, Masafumi Toriyabe, Itaru Ninomiya, Masahiro Hatakeyama, Masahiro Uemura, Osamu Onodera, Takayoshi Shimohata, Masato Kanazawa

Journal of the neurological sciences 419 117217 - 117217 2020年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Reperfusion therapies by tissue plasminogen activator (tPA) and mechanical thrombectomy (MT) have ushered in a new era in the treatment of acute ischemic stroke (AIS). However, reperfusion therapy-related HT remains an enigma. AIM: To provide a comprehensive review focused on emerging concepts of stroke and therapeutic strategies, including the use of protective agents to prevent HT after reperfusion therapies for AIS. METHODS: A literature review was performed using PubMed and the ClinicalTrials.gov database. RESULTS: Risk of HT increases with delayed initiation of tPA treatment, higher baseline glucose level, age, stroke severity, episode of transient ischemic attack within 7 days of stroke onset, and hypertension. At a molecular level, HT that develops after thrombolysis is thought to be caused by reactive oxygen species, inflammation, remodeling factor-mediated effects, and tPA toxicity. Modulation of these pathophysiological mechanisms could be a therapeutic strategy to prevent HT after tPA treatment. Clinical mechanisms underlying HT after MT are thought to involve smoking, a low Alberta Stroke Program Early CT Score, use of general anesthesia, unfavorable collaterals, and thromboembolic migration. However, the molecular mechanisms are yet to be fully investigated. Clinical trials with MT and protective agents have also been planned and good outcomes are expected. CONCLUSION: To fully utilize the easily accessible drug-tPA-and the high recanalization rate of MT, it is important to reduce bleeding complications after recanalization. A future study direction could be to investigate the recovery of neurological function by combining reperfusion therapies with cell therapies and/or use of pleiotropic protective agents.

DOI： 10.1016/j.jns.2020.117217

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Progressive supranuclear palsy: Neuropathology of patients with a short disease duration due to unexpected death 国際誌

Lu Zhang, Yasuko Toyoshima, Akari Takeshima, Hiroshi Shimizu, Itsuro Tomita, Osamu Onodera, Hitoshi Takahashi, Akiyoshi Kakita

NEUROPATHOLOGY 41 ( 3 ) 174 - 182 2020年11月

Association between serum IgG antibody titers against Porphyromonas gingivalis and liver enzyme levels: A cross-sectional study in Sado Island. 国際誌

Kei Takamisawa, Noriko Sugita, Shigeki Komatsu, Minako Wakasugi, Akio Yokoseki, Akihiro Yoshihara, Tetsuo Kobayashi, Kazutoshi Nakamura, Osamu Onodera, Takeshi Momotsu, Naoto Endo, Kenji Sato, Ichiei Narita, Hiromasa Yoshie, Koichi Tabeta

Heliyon 6 ( 11 ) e05531 2020年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

Background: Previous studies have reported associations between nonalcoholic fatty liver disease, periodontitis, and obesity. Serum immunoglobulin G (IgG) antibody titer against Porphyromonas gingivalis, a major pathogen of periodontitis, is an established indicator of periodontal infection. However, the relationship between the antibody titer and liver enzyme levels has not been clarified yet. A study in the elderly was needed to evaluate the effect of long-term persistent bacterial infection on liver function. The objective of this study was to investigate the association between liver function and infection by P. gingivalis, and the effect of obesity on the association. Methods: A cross-sectional study was conducted in adult outpatients visiting Sado General Hospital, in Niigata Prefecture, Japan, from 2008 to 2010. The final participants included 192 men and 196 women (mean age 68.1 years). Multivariable logistic regression analyses were performed to assess the association between the serum IgG antibody titer and the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamine transferase (GGT) levels. Results: In women, serum IgG antibody titers against P. gingivalis was associated with elevated ALT, but not with AST or GGT, independent of covariates (p = 0.015). No significant association was found between the antibody titer and the elevated liver enzymes in men. The effect of obesity on the relationship between antibody titer and liver enzyme levels was not statistically significant. Conclusions: A cross-sectional analysis of adult outpatients suggested an association between P. gingivalis infection and ALT levels in women. The effect of obesity on this association was not statistically significant.

DOI： 10.1016/j.heliyon.2020.e05531

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筋萎縮性側索硬化症の確定診断までの時間に与える、初診科、発症部位の検討

大津裕, 小池佑佳, 石原智彦, 小野寺理

臨床神経学 60 ( Suppl. ) S380 - S380 2020年11月

神経疾患・精神疾患の鑑別における血漿炎症性サイトカインの有用性

樋口陽, 春日健作, 徳武孝允, 宮下哲典, 茂木崇治, 福井直樹, 横山裕一, 染矢俊幸, 小野寺理, 池内健

臨床神経学 60 ( Suppl. ) S377 - S377 2020年11月

日本におけるSOD1遺伝子変異陽性筋萎縮性側索硬化症患者の臨床的特徴

中村亮一, 熱田直樹, 藤内玄規, 林直毅, 勝野雅央, 和泉唯信, 金井数明, 服部信孝, 谷口彰, 森田光哉, 狩野修, 澁谷和幹, 桑原聡, 鈴木直輝, 青木正志, 阿部康二, 石原智彦, 小野寺理, 梶龍兒, 祖父江元

臨床神経学 60 ( Suppl. ) S381 - S381 2020年11月

CADASIL原因遺伝子NOTCH3のシステイン非関連variant p.Val237Metの病的意義の検討

水田依久子, 加納裕也, 植田明彦, 野崎洋明, 櫻井圭太, 小野寺理, 安東由喜雄, 湯浅浩之, 水野敏樹

臨床神経学 60 ( Suppl. ) S421 - S421 2020年11月

CADASIL原因遺伝子NOTCH3のシステイン非関連variant p.Val237Metの病的意義の検討

水田依久子, 加納裕也, 植田明彦, 野崎洋明, 櫻井圭太, 小野寺理, 安東由喜雄, 湯浅浩之, 水野敏樹

臨床神経学 60 ( Suppl. ) S421 - S421 2020年11月

多系統萎縮症における脳脊髄液中NG2とα-シヌクレインの検討

徳武孝允, 春日健作, 月江珠緒, 樋口陽, 下畑享良, 小野寺理, 池内健

臨床神経学 60 ( Suppl. ) S433 - S433 2020年11月

ALS剖検例に関するテキストマイニングとエキソーム分析を用いたALSの新規候補遺伝子の探索(Search for new candidate genes for ALS by textmining and exome analysis of autopsy cases)

Hatano Yuya, Ishihara Tomohiko, Yokoseki Akio, Tada Mari, Kakita Akiyoshi, Okuda Shujiro, Onodera Osamu

臨床神経学 60 ( Suppl. ) S324 - S324 2020年11月

散発性ALSの137症例における剖検物のエキソーム分析(Exome analysis in 137 autopsied sporadic ALS cases)

Ishihara Tomohiko, Hatano Yuya, Yokoseki Akio, Tada Mari, Nakajima Takashi, Koike Ryoko, Kakita Akiyoshi, Onodera Osamu

臨床神経学 60 ( Suppl. ) S309 - S309 2020年11月

[Cell Therapy Using Peripheral Mononuclear Cells Preconditioned by Oxygen-Glucose Deprivation for Ischemic Stroke].

Masahiro Hatakeyama, Itaru Ninomiya, Osamu Onodera, Takayoshi Shimohata, Masato Kanazawa

Brain and nerve = Shinkei kenkyu no shinpo 72 ( 10 ) 1097 - 1103 2020年10月

記述言語：日本語掲載種別：研究論文（学術雑誌）

Many studies in recent years have reported cell therapies using embryonic stem cells, induced pluripotent stem cells, and bone marrow-derived mononuclear cells for cerebral ischemia. However, obtaining these cells is challenging, and these cell therapies require complicated procedures to prepare cells for administration. Notably, peripheral blood mononuclear cells (PBMCs) are a useful cell source for clinical applications because cell collection is easier. In this review, we report the therapeutic effects of PBMCs preconditioned by oxygen-glucose deprivation (OGD-PBMCs) on cerebral ischemia. Cell therapies using tissue-protective OGD-PBMCs might be a simple and ideal therapeutic strategy against ischemic stroke.

DOI： 10.11477/mf.1416201655

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本邦におけるCADASILの全国調査と多施設データベースの構築

新堂晃大, 田部井賢一, 谷口彰, 小野寺理, 安東由喜雄, 卜部貴夫, 北川一夫, 羽生春夫, 平野照之, 脇田英明, 福山秀直, 鍵村達夫, 宮本恵宏, 竹上未紗, 水田依久子, 猪原匡史, 水野敏樹, 冨本秀和

Dementia Japan 34 ( 4 ) 491 - 491 2020年10月

本邦におけるCADASILの全国調査と多施設データベースの構築

Dementia Japan 34 ( 4 ) 491 - 491 2020年10月

実は見逃されている血管性認知症の危険因子

山下徹, 野崎洋明, 涌谷陽介, 田所功, 野村恵美, 菱川望, 武本麻美, 太田康之, 小野寺理, 阿部康二

Dementia Japan 34 ( 4 ) 493 - 493 2020年10月

A multi-ethnic meta-analysis identifies novel genes, including ACSL5, associated with amyotrophic lateral sclerosis. 国際誌

Ryoichi Nakamura, Kazuharu Misawa, Genki Tohnai, Masahiro Nakatochi, Sho Furuhashi, Naoki Atsuta, Naoki Hayashi, Daichi Yokoi, Hazuki Watanabe, Hirohisa Watanabe, Masahisa Katsuno, Yuishin Izumi, Kazuaki Kanai, Nobutaka Hattori, Mitsuya Morita, Akira Taniguchi, Osamu Kano, Masaya Oda, Kazumoto Shibuya, Satoshi Kuwabara, Naoki Suzuki, Masashi Aoki, Yasuyuki Ohta, Toru Yamashita, Koji Abe, Rina Hashimoto, Ikuko Aiba, Koichi Okamoto, Kouichi Mizoguchi, Kazuko Hasegawa, Yohei Okada, Tomohiko Ishihara, Osamu Onodera, Kenji Nakashima, Ryuji Kaji, Yoichiro Kamatani, Shiro Ikegawa, Yukihide Momozawa, Michiaki Kubo, Noriko Ishida, Naoko Minegishi, Masao Nagasaki, Gen Sobue

Communications biology 3 ( 1 ) 526 - 526 2020年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

Amyotrophic lateral sclerosis (ALS) is a devastating progressive motor neuron disease that affects people of all ethnicities. Approximately 90% of ALS cases are sporadic and thought to have multifactorial pathogenesis. To understand the genetics of sporadic ALS, we conducted a genome-wide association study using 1,173 sporadic ALS cases and 8,925 controls in a Japanese population. A combined meta-analysis of our Japanese cohort with individuals of European ancestry revealed a significant association at the ACSL5 locus (top SNP p = 2.97 × 10-8). We validated the association with ACSL5 in a replication study with a Chinese population and an independent Japanese population (1941 ALS cases, 3821 controls; top SNP p = 1.82 × 10-4). In the combined meta-analysis, the intronic ACSL5 SNP rs3736947 showed the strongest association (p = 7.81 × 10-11). Using a gene-based analysis of the full multi-ethnic dataset, we uncovered additional genes significantly associated with ALS: ERGIC1, RAPGEF5, FNBP1, and ATXN3. These results advance our understanding of the genetic basis of sporadic ALS.

DOI： 10.1038/s42003-020-01251-2

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クエチアピン単剤化により精神症状と運動症状が改善したハンチントン病による認知症の1例

宮下真子, 渡部雄一郎, 本郷祥子, 小池直人, 佐治越爾, 深石翔, 三上剛明, 小野寺理, 染矢俊幸

精神神経学雑誌 ( 2020特別号 ) S313 - S313 2020年9月

Cell Therapies under Clinical Trials and Polarized Cell Therapies in Pre-Clinical Studies to Treat Ischemic Stroke and Neurological Diseases: A Literature Review. 査読国際誌

Masahiro Hatakeyama, Itaru Ninomiya, Yutaka Otsu, Kaoru Omae, Yasuko Kimura, Osamu Onodera, Masanori Fukushima, Takayoshi Shimohata, Masato Kanazawa

International journal of molecular sciences 21 ( 17 ) 2020年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

Stroke remains a major cause of serious disability because the brain has a limited capacity to regenerate. In the last two decades, therapies for stroke have dramatically changed. However, half of the patients cannot achieve functional independence after treatment. Presently, cell-based therapies are being investigated to improve functional outcomes. This review aims to describe conventional cell therapies under clinical trial and outline the novel concept of polarized cell therapies based on protective cell phenotypes, which are currently in pre-clinical studies, to facilitate functional recovery after post-reperfusion treatment in patients with ischemic stroke. In particular, non-neuronal stem cells, such as bone marrow-derived mesenchymal stem/stromal cells and mononuclear cells, confer no risk of tumorigenesis and are safe because they do not induce rejection and allergy; they also pose no ethical issues. Therefore, recent studies have focused on them as a cell source for cell therapies. Some clinical trials have shown beneficial therapeutic effects of bone marrow-derived cells in this regard, whereas others have shown no such effects. Therefore, more clinical trials must be performed to reach a conclusion. Polarized microglia or peripheral blood mononuclear cells might provide promising therapeutic strategies after stroke because they have pleiotropic effects. In traumatic injuries and neurodegenerative diseases, astrocytes, neutrophils, and T cells were polarized to the protective phenotype in pre-clinical studies. As such, they might be useful therapeutic targets. Polarized cell therapies are gaining attention in the treatment of stroke and neurological diseases.

DOI： 10.3390/ijms21176194

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Novel CHP1 mutation in autosomal-recessive cerebellar ataxia: autopsy features of two siblings. 査読国際誌

Rie Saito, Norikazu Hara, Mari Tada, Yoshiaki Honma, Akinori Miyashita, Osamu Onodera, Takeshi Ikeuchi, Akiyoshi Kakita

Acta neuropathologica communications 8 ( 1 ) 134 - 134 2020年8月

[Dural arteriovenous fistula causing complex visual hallucinations without an anopsia]. 査読

Shingo Koide, Masahiro Hatakeyama, Masahiro Uemura, Bumpei Kikuchi, Hitoshi Hasegawa, Osamu Onodera

Rinsho shinkeigaku = Clinical neurology 60 ( 6 ) 425 - 428 2020年6月

記述言語：日本語掲載種別：研究論文（学術雑誌）

We report the case of a 76-year-old woman who presented with recurrent episodes of complex visual hallucinations in her right visual field without an anopsia. The electroencephalogram showed sharp transients in the left parietotemporal region with phase reversals at T5 and P3. FLAIR MRI revealed hyperintense lesions in the left temporo-occipital lobe, located mainly in the left inferior temporal lobe. Cerebral angiography revealed an arteriovenous shunt from the left occipital artery to the left transverse sinus with cortical venous reflux. The complex visual hallucinations were resolved after transarterial embolization. We therefore hypothesize that this patient's complex visual hallucinations were caused by epileptic seizures or changes in cortical blood flow caused by the cortical venous reflux from the arteriovenous fistula. In general, epileptic hallucinations expand into the bilateral visual field. We reveal that in rare cases, complex visual hallucinations can also be limited to the unilateral visual field without an anopsia. Additionally, we reveal that a dural arteriovenous fistula can cause visual hallucinations without hemianopia.

DOI： 10.5692/clinicalneurol.60.cn-001371

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Oculopharyngodistal myopathy with coexisting histology of systemic neuronal intranuclear inclusion disease: Clinicopathologic features of an autopsied patient harboring CGG repeat expansions in LRP12. 査読国際誌

Rie Saito, Hiroshi Shimizu, Takeshi Miura, Norikazu Hara, Naomi Mezaki, Yo Higuchi, Akinori Miyashita, Izumi Kawachi, Kazuhiro Sanpei, Yoshiaki Honma, Osamu Onodera, Takeshi Ikeuchi, Akiyoshi Kakita

Acta neuropathologica communications 8 ( 1 ) 75 - 75 2020年6月

Refractory Myositis Affecting the Intrinsic Muscles of the Hand. 査読

Kosei Nakamura, Akihiro Sugai, Etsuji Saji, Kensaku Kasuga, Osamu Onodera

Internal medicine (Tokyo, Japan) 59 ( 9 ) 1211 - 1214 2020年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

Myositis generally affects the proximal muscles. However, we herein report a case of a 48-year-old woman with intractable myositis affecting the intrinsic muscles of the hands. Her myositis, which developed in childhood, was refractory to treatment with steroids and several immunosuppressants, causing walking disability. After experiencing pain and swelling in the hands for six months, she was diagnosed with myositis of the intrinsic muscles of the hands and tested positive for the anti-signal recognition particle antibody. Intravenous immunoglobulin therapy improved the myositis of the hands. This case suggests that inflammation caused by intractable myositis can extend to the hands.

DOI： 10.2169/internalmedicine.3773-19

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[Amyloid β-related angiitis presenting extensive brain involvement without detection of hemorrhagic lesions: A case report]. 査読

Yuya Hatano, Akihiro Sugai, Takuma Yamagishi, Akihiro Nakajima, Akiyoshi Kakita, Osamu Onodera

Rinsho shinkeigaku = Clinical neurology 60 ( 3 ) 187 - 192 2020年3月

記述言語：日本語掲載種別：研究論文（学術雑誌）

In amyloid β-related angiitis, cortical or subcortical microbleeding or cortical superficial siderosis supports clinical diagnosis. However, here we present a 75-year-old female case of amyloid β-related angiitis that did not initially show these lesions. The patient developed right homonymous hemianopia and aphasia, and subsequently became comatose. Her brain lesions progressed extensively from the left occipital lobe to the bilateral cerebral hemispheres, with diffused leptomeningeal lesions and scattered DWI high-intensity lesions. After pathological diagnosis, steroid treatment improved her symptoms as well as imaging findings. No hemorrhagic lesions were detected in the T2*-weighted imaging performed before treatment. However, susceptibility-weighted imaging performed after treatment showed a number of lesions with microbleeding. The clinical features of amyloid β-related angiitis that do not show hemorrhagic lesions at onset should be investigated for rapid therapeutic intervention in the future.

DOI： 10.5692/clinicalneurol.cn-001340

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新規抗てんかん薬トピラマートのラット骨代謝に及ぼす影響

神田循吉, 出雲信夫, 古川恵, 島倉剛俊, 山本智章, 小野寺憲治, 若林広行

日本薬学会年会要旨集 140年会 27Q - am056 2020年3月

[Molecular mechanism of amyotrophic lateral sclerosis (ALS) from the viewpoint of the formation and degeneration of transactive response DNA-binding protein 43 kDa (TDP-43) inclusions]. 査読

Sou Kasahara, Tomohiko Ishihara, Yuka Koike, Akihiro Sugai, Osamu Onodera

Rinsho shinkeigaku = Clinical neurology 60 ( 2 ) 109 - 116 2020年2月

記述言語：日本語掲載種別：研究論文（学術雑誌）

Sporadic amyotrophic lateral sclerosis (SALS) and many cases of familial ALS (FALS) demonstrate cytoplasmic transactive response DNA-binding protein 43 kDa (TDP-43)-positive inclusion bodies. Thus, TDP-43 plays a vital role in ALS pathogenesis. Functional analysis of the ALS causative genes advanced the elucidation of the mechanism associated with the formation and degradation of TDP-43 aggregates. Stress granules, which are non-membranous organelles, are attracting attention as sites of aggregate formation, with involvement of FUS and C9orf72. Concurrently, ALS causative genes related to the ubiquitin-proteasome and autophagy systems, which are aggregate degradation mechanisms, have also been reported. Therefore, therapeutic research based on the molecular pathology common to SALS and FALS has been advanced.

DOI： 10.5692/clinicalneurol.cn-001362

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Hemorrhagic cerebral small vessel disease caused by a novel mutation in 3' UTR of collagen type IV alpha 1. 査読国際誌

Naoko Sakai, Masahiro Uemura, Taisuke Kato, Hiroaki Nozaki, Akihide Koyama, Shouichirou Ando, Hiroyuki Kamei, Motohiro Kato, Osamu Onodera

Neurology. Genetics 6 ( 1 ) e383 2020年2月

Transactive response DNA-binding protein 43kDa(TDP-43)凝集体の形成と分解からみたamyotrophic lateral sclerosis(ALS)の分子機構査読

笠原壮, 石原智彦, 小池佑佳, 須貝章弘, 小野寺理

臨床神経学 60 ( 2 ) 109 - 116 2020年2月

Frequencies of Hereditary Cerebral Small Vessel Diseases Among Patients With Adult-Onset Leukoencephalopathy

Masahiro Uemura, Hiroaki Nozaki, Naoko Sakai, Shouichirou Ando, Masato Kanazawa, Hajime Kondo, Akira Iwanaga, Hiroyuki Murota, Takeshi Ikeuchi, Ikuko Mizuta, Toshiki Mizuno, Osamu Onodera

STROKE 51 2020年2月

Role of RNF213 p.4810K variant in the development of intracranial arterial disease in patients treated with nilotinib. 査読国際誌

Masahiro Uemura, Masato Kanazawa, Takuma Yamagishi, Takahiro Nagai, Mami Takahashi, Shingo Koide, Masayoshi Tada, Junsuke Shimbo, Aiko Isami, Kunihiko Makino, Masayoshi Masuko, Kouji Nikkuni, Kouichirou Okamoto, Shuichi Igarashi, Kenichi Morita, Osamu Onodera

Journal of the neurological sciences 408 116577 - 116577 2020年1月

Progressive Supranuclear Palsy with Predominant Cerebellar Ataxia. 査読国際誌

Shoichiro Ando, Masato Kanazawa, Osamu Onodera

Journal of movement disorders 13 ( 1 ) 20 - 26 2020年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

Progressive supranuclear palsy (PSP) is characterized by supranuclear gaze palsy, dystonic rigidity of the neck and upper trunk, frequent falls and mild cognitive impairment. Cerebellar ataxia is one of the exclusion criteria given by the National Institute of Neurological Disorders and Stroke and the Society for Progressive Supranuclear Palsy. As a result, pathologically proven PSP patients exhibiting cerebellar ataxia have often been misdiagnosed with spinocerebellar degeneration, specifically multiple system atrophy with predominant cerebellar ataxia (MSA-C). However, more recently, it has been recognized that patients with PSP can present with truncal and limb ataxia as their initial symptom and/or main manifestation. These patients can be classified as having PSP with predominant cerebellar ataxia (PSP-C), a new subtype of PSP. Since the development of this classification, patients with PSP-C have been identified primarily in Asian countries, and it has been noted that this condition is very rare in Western communities. Furthermore, the clinical features of PSP-C have been identified, enabling it to be distinguished from other subtypes of PSP and MSA-C. In this review, we describe the clinical and neuropathological features of PSP-C. The hypothesized pathophysiology of cerebellar ataxia in PSP-C is also discussed.

DOI： 10.14802/jmd.19061

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Excessive Production of Transforming Growth Factor β1 Causes Mural Cell Depletion From Cerebral Small Vessels. 査読国際誌

Taisuke Kato, Yumi Sekine, Hiroaki Nozaki, Masahiro Uemura, Shoichiro Ando, Sachiko Hirokawa, Osamu Onodera

Frontiers in aging neuroscience 12 151 - 151 2020年

記述言語：英語掲載種別：研究論文（学術雑誌）

It is increasingly becoming apparent that cerebrovascular dysfunction contributes to the pathogenic processes involved in vascular dementia, Alzheimer's disease, and other neurodegenerative disorders. Under these pathologic conditions, the degeneration of cerebral blood vessels is frequently accompanied by a loss of mural cells from the vascular walls. Vascular mural cells play pivotal roles in cerebrovascular functions, such as regulation of cerebral blood flow and maintenance of the blood-brain barrier (BBB). Therefore, cerebrovascular mural cell impairment is involved in the pathophysiology of vascular-related encephalopathies, and protecting these cells is essential for maintaining brain health. However, our understanding of the molecular mechanism underlying mural cell abnormalities is incomplete. Several reports have indicated that dysregulated transforming growth factor β (TGFβ) signaling is involved in the development of cerebral arteriopathies. These studies have specifically suggested the involvement of TGFβ overproduction. Although cerebrovascular toxicity via vascular fibrosis by extracellular matrix accumulation or amyloid deposition is known to occur with enhanced TGFβ production, whether increased TGFβ results in the degeneration of vascular mural cells in vivo remains unknown. Here, we demonstrated that chronic TGFβ1 overproduction causes a dropout of mural cells and reduces their coverage on cerebral vessels in both smooth muscle cells and pericytes. Mural cell degeneration was also accompanied by vascular luminal dilation. TGFβ1 overproduction in astrocytes significantly increased TGFβ1 content in the cerebrospinal fluid (CSF) and increased TGFβ signaling-regulated gene expression in both pial arteries and brain capillaries. These results indicate that TGFβ is an important effector that mediates mural cell abnormalities under pathological conditions related to cerebral arteriopathies.

DOI： 10.3389/fnagi.2020.00151

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A Nationwide Survey and Multicenter Registry-Based Database of Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy in Japan. 査読国際誌

Akihiro Shindo, Ken-Ichi Tabei, Akira Taniguchi, Hiroaki Nozaki, Osamu Onodera, Akihiko Ueda, Yukio Ando, Takao Urabe, Kazumi Kimura, Kazuo Kitagawa, Haruo Hanyu, Teruyuki Hirano, Hideaki Wakita, Hidenao Fukuyama, Tatsuo Kagimura, Yoshihiro Miyamoto, Misa Takegami, Satoshi Saito, Akiko Watanabe-Hosomi, Ikuko Mizuta, Masafumi Ihara, Toshiki Mizuno, Hidekazu Tomimoto

Frontiers in aging neuroscience 12 216 - 216 2020年

記述言語：英語掲載種別：研究論文（学術雑誌）

Objectives: Clinical characteristics of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) include migraine, recurrent stroke, white matter lesions, and vascular dementia. CADASIL is one of the most common hereditary cerebral small vessel diseases. Clinical presentation of CADASIL varies and a racial gap may exist between the Asian and Caucasian populations. This is the first nationwide epidemiological survey which aimed to elucidate the clinical features of CADASIL in Japan. Moreover, the registration database of CADASIL was constructed. Methods: Subjects included CADASIL patients who visited the hospitals (totally 1,448 hospitals) certified by the Japanese Society of Neurology and/or Japan Stroke Society in 2016. This study consisted of a two-step survey; patients with CADASIL were identified genetically by the first questionnaire, and their clinical features were assessed by the second questionnaire. Selected 6 hospitals registered the data of all CADASIL patients using a Research Electronic Data Capture (REDCap) system for the second questionnaire. Results: Based on the criteria, 88 patients (50 male and 38 female) with CADASIL were enrolled. The mean age of symptom onset was 49.5 years. Sixteen (18.2%) patients had an elderly onset (>60 years). Thirteen patients (13.6%) had history of migraine with aura and 33 patients (37.5%) had vascular risk factor(s). From among the 86 patients who were examined using magnetic resonance imaging, abnormal deep white matter lesions were detected in 85 patients (98.8%), WMLs extending to anterior temporal pole in 73 patients (84.9%), and cerebral microbleeds in 41 patients (47.7%). Anti-platelet therapy was received by 65 patients (73.9%). Thirty-eight patients (43.2%) underwent treatment with lomerizine hydrochloride. Thirty-four different mutations of NOTCH3 were found in exons 2, 3, 4, 5, 6, 8, 11, 14, and 19. Most of the mutations existed in exon 4 (n = 44, 60.3%). The prevalence rate of CADASIL was 1.20 to 3.58 per 100,000 adults in Japan. Conclusion: This questionnaire-based study revealed clinical features and treatment status in Japanese CADASIL patient, although it may not be an exhaustive search. We have constructed the REDCap database for these CADASIL patients.

DOI： 10.3389/fnagi.2020.00216

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Publisher Correction: A novel therapeutic approach using peripheral blood mononuclear cells preconditioned by oxygen-glucose deprivation. 査読国際誌

Masahiro Hatakeyama, Masato Kanazawa, Itaru Ninomiya, Kaoru Omae, Yasuko Kimura, Tetsuya Takahashi, Osamu Onodera, Masanori Fukushima, Takayoshi Shimohata

Scientific reports 9 ( 1 ) 19913 - 19913 2019年12月

TAF15が主要に蓄積したFET病理を伴う筋萎縮性側索硬化症剖検例の臨床病理学的特徴(Amsotrophic lateral sclerosis with TAF15-predominant FET pathology: clinicopathologic features of an autopsied patient)

Cui Bo, Tada Mari, Hatano Yuya, Takeshima Akari, Ishihara Tomohiko, Sugai Akihiro, Tokutake Takayoshi, Kanazawa Masato, Onodera Osamu, Kakita Akiyoshi

新潟医学会雑誌 133 ( 11-12 ) 391 - 391 2019年12月

A novel therapeutic approach using peripheral blood mononuclear cells preconditioned by oxygen-glucose deprivation. 査読国際誌

Masahiro Hatakeyama, Masato Kanazawa, Itaru Ninomiya, Kaoru Omae, Yasuko Kimura, Tetsuya Takahashi, Osamu Onodera, Masanori Fukushima, Takayoshi Shimohata

Scientific reports 9 ( 1 ) 16819 - 16819 2019年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

Cell therapies that invoke pleiotropic mechanisms may facilitate functional recovery in patients with stroke. Based on previous experiments using microglia preconditioned by oxygen-glucose deprivation, we hypothesized that the administration of peripheral blood mononuclear cells (PBMCs) preconditioned by oxygen-glucose deprivation (OGD-PBMCs) to be a therapeutic strategy for ischemic stroke. Here, OGD-PBMCs were identified to secrete remodelling factors, including the vascular endothelial growth factor and transforming growth factor-β in vitro, while intra-arterial administration of OGD-PBMCs at 7 days after focal cerebral ischemia prompted expression of such factors in the brain parenchyma at 28 days following focal cerebral ischemia in vivo. Furthermore, administration of OGD-PBMCs induced an increasing number of stage-specific embryonic antigen-3-positive cells both in vitro and in vivo. Finally, it was found to prompt angiogenesis and axonal outgrowth, and functional recovery after cerebral ischemia. In conclusion, the administration of OGD-PBMCs might be a novel therapeutic strategy against ischemic stroke.

DOI： 10.1038/s41598-019-53418-5

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[Molecular Pathogenesis of Amyotrophic Lateral Sclerosis]. 査読

Shintaro Tsuboguchi, Tomohiko Ishihara, Akihiro Sugai, Akio Yokoseki, Osamu Onodera

Brain and nerve = Shinkei kenkyu no shinpo 71 ( 11 ) 1183 - 1189 2019年11月

記述言語：日本語掲載種別：研究論文（学術雑誌）

The molecular pathogenesis of amyotrophic lateral sclerosis (ALS) has been studied through analysis of the function of the protein produced by the causative genes of familial ALS. The products of these genes are classified as RNA binding proteins, or proteins related to proteolytic systems. However, most case of familial ALS, and sporadic ALS show TAR DNA binding protein-43 (TDP-43) immune-positive cytoplasmic inclusions. Therefore, the molecular mechanism of formation of TDP-43 inclusions and dysfunction caused by TDP-43 inclusions has been studied. As for the mechanism of inclusion formation, non-membrane organelle formation by liquid-liquid phase separation (LLPS) is important. The ubiquitin-proteasome and autophagy systems are important for the degradation of these inclusions. Several genes associated with these systems have been identified as causative genes for ALS. The formation of cytoplasmic inclusions results in the loss of TDP-43 from the nucleus, resulting in abnormalities in RNA metabolism, through the alteration of spliceosomes and Gemini of coiled bodies. Furthermore, in ALS, the regulation of TDP-43 mRNA/protein expression levels has failed. Failure of the autoregulation system facilitates TDP-43 inclusion formation. Development of treatments for ALS based on these elucidated molecular mechanisms is desirable.

DOI： 10.11477/mf.1416201428

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【ALS 2019】TDP-43封入体から解くALSの分子病態査読

坪口晋太朗, 石原智彦, 須貝章弘, 横関明男, 小野寺理

BRAIN and NERVE: 神経研究の進歩 71 ( 11 ) 1183 - 1189 2019年11月

Shrinkage of the myenteric neurons of the small intestine in patients with multiple system atrophy. 査読国際誌

Tetsutaro Ozawa, Hiroshi Shimizu, Hideaki Matsui, Osamu Onodera, Akiyoshi Kakita

Autonomic neuroscience : basic & clinical 221 102583 - 102583 2019年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

This study aimed to determine whether enteric neurons are involved in multiple system atrophy (MSA). Four-μm-thick slices of small intestine were prepared from 10%-formalin-fixed and paraffin-embedded materials obtained from autopsied cases. Enteric neurons were stained using an anti-peripherin antibody. Immunostaining of phosphorylated α-synuclein was also performed. Areas of the cytoplasm and nucleus that showed nucleoli were measured using computer software. Both areas of myenteric neurons were significantly smaller in MSA cases (n = 3) than in control subjects (n = 3) (P < 0.0001); however, no deposits of phosphorylated α-synuclein were observed. These findings suggest that myenteric neurons in MSA are affected independent of α-synuclein accumulation.

DOI： 10.1016/j.autneu.2019.102583

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HTRA1 Disorder

Onodera O, Nozaki H, Fukutake T

2019年11月

PSP症例におけるPSP評価尺度と臨床診断の縦断研究(Longitudinal study of PSP rating scale and clinical diagnosis in PSP cases)

Takigawa Hiroshi, Ikeuchi Takeshi, Aiba Ikuko, Morita Mitsuya, Onodera Osamu, Shimohata Takayoshi, Tokuda Takahiko, Murayama Shigeo, Hasegawa Kazuko, Kowa Hisanori, Tokumaru Aya M., Hanajima Ritsuko, Nakashima Kenji, JALPAC study group

臨床神経学 59 ( Suppl. ) S245 - S245 2019年11月

ALS患者の生存期間に与える非侵襲的換気補助療法の影響レジストリを用いた解析

熱田直樹, 横井大知, 平川晃弘, 林直毅, 中村良一, 伊藤瑞規, 渡辺宏久, 勝野雅央, 和泉唯信, 森田光哉, 谷口彰, 狩野修, 桑原聡, 青木正志, 金井数明, 小野寺理, 梶龍兒, 祖父江元, JaCALS

臨床神経学 59 ( Suppl. ) S358 - S358 2019年11月

APP処理に対し時間・程度依存性の神経細胞活性化が及ぼす影響(Time- and extent- dependent effect of neuronal activation on APP processing)

Ishiguro Takanobu, Kasuga Kensaku, Saito Kento, Mezaki Naomi, Miura Takeshi, Tokutake Takayoshi, Onodera Osamu, Ikeuchi Takeshi

臨床神経学 59 ( Suppl. ) S411 - S411 2019年11月

Phosphorylated TDP-43 aggregates in skeletal and cardiac muscle are a marker of myogenic degeneration in amyotrophic lateral sclerosis and various conditions. 査読国際誌

Fumiaki Mori, Mari Tada, Tomoya Kon, Yasuo Miki, Kunikazu Tanji, Hidekachi Kurotaki, Masahiko Tomiyama, Tomohiko Ishihara, Osamu Onodera, Akiyoshi Kakita, Koichi Wakabayashi

Acta neuropathologica communications 7 ( 1 ) 165 - 165 2019年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterized pathologically by the occurrence of phosphorylated TDP-43 (pTDP-43)-immunoreactive neuronal and glial inclusions in the central nervous system. Recent studies have shown that pTDP-43 aggregates also occur in the skeletal muscles in a certain proportion of ALS patients. AIM: The aim of this study was to clarify the distribution and incidence of pTDP-43 aggregates in the skeletal and cardiac muscles of patients with ALS, and also those of patients with neuromuscular diseases (NMDs) and non-NMDs. MATERIAL AND METHODS: Five regions of muscle (tongue, cervical muscle, diaphragm, iliopsoas muscle and heart) were examined histologically and immunohistochemically in patients with ALS (n = 30), NMDs (n = 13) and non-NMDs (n = 7). RESULTS: Two types of pTDP-43 aggregates were distinguishable morphologically: dense filamentous and short linear inclusions. These inclusions were found in at least one of the five muscle regions in all 30 cases of ALS; skeletal muscles in 28 cases and myocardium in 12. pTDP-43 aggregates were also found in 9 of 13 patients with NMDs, including myositis, muscular dystrophy and mitochondrial myopathy, as well as in 3 of 7 patients with non-NMDs. In ALS, pTDP-43 aggregates were most frequent in the diaphragm (19 cases). The mean density of pTDP-43 aggregates in ALS was significantly higher than that in NMDs and non-NMDs. In contiguous sections stained with hematoxylin and eosin and anti-pTDP-43, muscle fibers with dense filamentous inclusions demonstrated single-fiber atrophy with vacuolar degeneration. CONCLUSION: The present findings indicate that pTDP-43 aggregates in skeletal and cardiac muscle are a myogenic pathological marker in multiple diseases including ALS.

DOI： 10.1186/s40478-019-0824-1

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Morphological characterisation of glial and neuronal tau pathology in globular glial tauopathy (Types II and III). 査読国際誌

H Tanaka, Y Toyoshima, S Kawakatsu, R Kobayashi, O Yokota, S Terada, S Kuroda, T Miura, Y Higuchi, H Otsu, K Sanpei, K Otani, T Ikeuchi, O Onodera, A Kakita, H Takahashi

Neuropathology and applied neurobiology 2019年10月

記述言語：英語

AIMS: Globular glial tauopathy (GGT) is a new category within the 4-repeat tauopathies that is characterised neuropathologically by tau-positive globular glial inclusions (GGIs), namely, globular oligodendrocytic and astrocytic inclusions (GOIs and GAIs). Occurrence of tau-positive neuronal cytoplasmic inclusions (NCIs) is also a feature. GGT is classified into three pathological subtypes (Types I, II and III). We studied the tau pathology in 6 cases of GGT (Type II, n = 3; Type III, n = 3), with special reference to GAIs and NCIs. METHODS: Neuropathological examinations were conducted, along with immunohistochemistry, morphometry and three-dimensional imaging, and biochemical and genetic analysis of tau. RESULTS: The cortical GAIs in Type II and those in Type III were distinguishable from each other. In the motor cortex, GAIs were much more numerous in Type III than in Type II. Prominent occurrence of perikaryal globular structures was a feature of GAIs in Type III. By contrast, prominent occurrence of radiating process-like structures was a feature of GAIs in Type II. Overall, the GAIs were significantly smaller in Type III than in Type II. NCIs were divisible into three subgroups in terms of shape: diffuse granular, thick cord-like, and round/horseshoe-shaped structures. In all cases, NCIs were a feature of the upper and lower motor neurons. Interestingly, the round/horseshoe-shaped NCIs were observed only in Type III cases. CONCLUSIONS: These findings, which characterised GAIs and NCIs, indicated that Type II and Type III constitute two distinct pathological subtypes, and also further strengthen the concept of GGT as a distinct entity.

DOI： 10.1111/nan.12581

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Spinocerebellar Ataxia Type 17

Toyoshima Y, Onodera O, Yamada M, Tsuji S, Takahashi H

2019年9月

Ectopic Expression Induces Abnormal Somatodendritic Distribution of Tau in the Mouse Brain. 査読国際誌

Atsuko Kubo, Shouyou Ueda, Ayaka Yamane, Satoko Wada-Kakuda, Mai Narita, Makoto Matsuyama, Akane Nomori, Akihiko Takashima, Taisuke Kato, Osamu Onodera, Motohito Goto, Mamoru Ito, Takami Tomiyama, Hiroshi Mori, Shigeo Murayama, Yasuo Ihara, Hiroaki Misonou, Tomohiro Miyasaka

The Journal of neuroscience : the official journal of the Society for Neuroscience 39 ( 34 ) 6781 - 6797 2019年8月

記述言語：英語

Tau is a microtubule (MT)-associated protein that is localized to the axon. In Alzheimer's disease, the distribution of tau undergoes a remarkable alteration, leading to the formation of tau inclusions in the somatodendritic compartment. To investigate how this mislocalization occurs, we recently developed immunohistochemical tools that can separately detect endogenous mouse and exogenous human tau with high sensitivity, which allows us to visualize not only the pathological but also the pre-aggregated tau in mouse brain tissues of both sexes. Using these antibodies, we found that in tau-transgenic mouse brains, exogenous human tau was abundant in dendrites and somata even in the presymptomatic period, whereas the axonal localization of endogenous mouse tau was unaffected. In stark contrast, exogenous tau was properly localized to the axon in human tau knock-in mice. We tracked this difference to the temporal expression patterns of tau. Endogenous mouse tau and exogenous human tau in human tau knock-in mice exhibited high expression levels during the neonatal period and strong suppression into the adulthood. However, human tau in transgenic mice was expressed continuously and at high levels in adult animals. These results indicated the uncontrolled expression of exogenous tau beyond the developmental period as a cause of mislocalization in the transgenic mice. Superresolution microscopic and biochemical analyses also indicated that the interaction between MTs and exogenous tau was impaired only in the tau-transgenic mice, but not in knock-in mice. Thus, the ectopic expression of tau may be critical for its somatodendritic mislocalization, a key step of the tauopathy.SIGNIFICANCE STATEMENT Somatodendritic localization of tau may be an early step leading to the neuronal degeneration in tauopathies. However, the mechanisms of the normal axonal distribution of tau and the mislocalization of pathological tau remain obscure. Our immunohistochemical and biochemical analyses demonstrated that the endogenous mouse tau is transiently expressed in neonatal brains, that exogenous human tau expressed corresponding to such tau expression profile can distribute into the axon, and that the constitutive expression of tau into adulthood (e.g., human tau in transgenic mice) results in abnormal somatodendritic localization. Thus, the expression profile of tau is tightly associated with the localization of tau, and the ectopic expression of tau in matured neurons may be involved in the pathogenesis of tauopathy.

DOI： 10.1523/JNEUROSCI.2845-18.2019

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【細胞内の相分離タンパク質や核酸分子を整理し、反応の場を作り、生命を駆動する】ALS病態における液-液相分離と非膜性構造の異常査読

小池佑佳, 石原智彦, 小野寺理

実験医学 37 ( 9 ) 1416 - 1420 2019年6月

Angiogenesis in the ischemic core: A potential treatment target? 査読国際誌

Masato Kanazawa, Tetsuya Takahashi, Masanori Ishikawa, Osamu Onodera, Takayoshi Shimohata, Gregory J Del Zoppo

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 39 ( 5 ) 753 - 769 2019年5月

記述言語：英語

The ischemic penumbra is both a concept in understanding the evolution of cerebral tissue injury outcome of focal ischemia and a potential therapeutic target for ischemic stroke. In this review, we examine the evidence that angiogenesis can contribute to beneficial outcomes following focal ischemia in model systems. Several studies have shown that, following cerebral ischemia, endothelial proliferation and subsequent angiogenesis can be detected beginning four days after cerebral ischemia in the border of the ischemic core, or in the ischemic periphery, in rodent and non-human primate models, although initial signals appear within hours of ischemia onset. Components of the neurovascular unit, its participation in new vessel formation, and the nature of the core and penumbra responses to experimental focal cerebral ischemia, are considered here. The potential co-localization of vascular remodeling and axonal outgrowth following focal cerebral ischemia based on the definition of tissue remodeling and the processes that follow ischemic stroke are also considered. The region of angiogenesis in the ischemic core and its surrounding tissue (ischemic periphery) may be a novel target for treatment. We summarize issues that are relevant to model studies of focal cerebral ischemia looking ahead to potential treatments.

DOI： 10.1177/0271678X19834158

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Globular glial tauopathy Type II: Clinicopathological study of two autopsy cases. 査読国際誌

Hidetomo Tanaka, Shinobu Kawakatsu, Yasuko Toyoshima, Takeshi Miura, Naomi Mezaki, Atsushi Mano, Kazuhiro Sanpei, Ryota Kobayashi, Hiroshi Hayashi, Koichi Otani, Takeshi Ikeuchi, Osamu Onodera, Akiyoshi Kakita, Hitoshi Takahashi

Neuropathology : official journal of the Japanese Society of Neuropathology 39 ( 2 ) 111 - 119 2019年4月

記述言語：英語

Globular glial tauopathies (GGTs) are four-repeat tauopathies characterized by the presence of two types of tau-positive globular glial inclusions (GGIs): globular oligodendrocytic and astrocytic inclusions (GOIs and GAIs). GGTs are classified into three different neuropathological subtypes: Types I, II and III. We report two patients with GGTs - a 76-year-old woman and a 70-year-old man - in whom the disease duration was 5 and 6 years, respectively. Both patients exhibited upper and lower motor neuron signs and involuntary movements, and the latter also had dementia with frontotemporal cerebral atrophy evident on magnetic resonance imaging. Neuropathologically, in both cases, the precentral gyrus was most severely affected, and at the gray-white matter junction there was almost complete loss of Betz cells and occurrence of GOIs and coiled bodies with numerous neuropil threads. Both patients also showed neuronal loss and GGIs (mostly GOIs) in many other central nervous system regions, including the basal ganglia. Apart from the degree of regional severity, the distribution pattern was essentially the same in both cases. However, GAIs were not conspicuous in any of the affected regions. Based on the morphology and distribution pattern of the GGIs, we diagnosed the present two patients as having GGT Type II. Electron microscopic and biochemical findings in the former were consistent with the diagnosis. Type II cases are reported to be characterized by pyramidal features reflecting predominant motor cortex and corticospinal tract degeneration. The present observations suggest that a variety of neurological features, including dementia, can occur in GGT Type II reflecting widespread degeneration beyond the motor neuron system.

DOI： 10.1111/neup.12532

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Allogeneic stem cell transplantation with reduced intensity conditioning for patients with adrenoleukodystrophy. 査読国際誌

Koji Kato, Ryo Maemura, Manabu Wakamatsu, Ayako Yamamori, Motoharu Hamada, Shinsuke Kataoka, Atsushi Narita, Shunsuke Miwata, Yuko Sekiya, Nozomu Kawashima, Kyogo Suzuki, Kotaro Narita, Sayoko Doisaki, Hideki Muramatsu, Hirotoshi Sakaguchi, Kimikazu Matsumoto, Yuka Koike, Osamu Onodera, Makiko Kaga, Nobuyuki Shimozawa, Nao Yoshida

Molecular genetics and metabolism reports 18 1 - 6 2019年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

Objective: The prognosis of adrenoleukodystrophy (ALD)with neurological involvement is generally dismal; however, allogeneic stem cell transplantation (SCT) is recognized as effective to stabilize or improve the clinical symptoms of ALD. Herein, we report the clinical outcomes of patients with ALD who consecutively underwent allogeneic stem cell transplantation with reduced intensity conditioning at our institution. Patients: Sixteen patients with ALD, who were symptomatic (n = 14) or presymptomatic (n = 2), received SCT from 2010 to 2016. The stem cell source was cord blood (n = 14), or bone marrow from a human leukocyte antigen identical sibling (n = 2). The conditioning regimen prior to transplantation was reduced intensity and consisted of fludarabine (125 mg/m2), melphalan (140 mg/m2) and low dose total body irradiation (TBI) of 4Gy (n = 15) or 3Gy (n = 1). Results: Primary engraftment was obtained in 11 patients, and 4 of the 5 patients who lost the primary graft received a second cord blood transplantation and were engrafted. Five years overall and event-free survival were 90.9% and 61.1% respectively, with a median of 45 months (range 16-91). Loes score stabilized or improved by 18 months after transplantation except for patients with internal capsule involvement. Conclusion: Allogeneic SCT with reduced intensity conditioning for patients with ALD was safely performed without major transplant-related complications even in symptomatic patients and neurological symptoms were stabilized after SCT in patients without internal capsule involvement.

DOI： 10.1016/j.ymgmr.2018.11.001

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Low serum 25-hydroxyvitamin D increases cognitive impairment in elderly people. 査読

Mayumi Sakuma, Kaori Kitamura, Naoto Endo, Takeshi Ikeuchi, Akio Yokoseki, Osamu Onodera, Takeo Oinuma, Takeshi Momotsu, Kenji Sato, Kazutoshi Nakamura, Ichiei Narita

Journal of bone and mineral metabolism 37 ( 2 ) 368 - 375 2019年3月

記述言語：英語

It has been reported that many elderly people have low serum levels of 25-hydroxyvitamin D [25(OH)D] and that serum 25(OH)D levels may have a relationship with cognitive function. The aim of this study was to examine the relationship between serum 25(OH)D levels and cognitive function in a Japanese population. This cross-sectional study was performed as a part of the Project in Sado for Total Health (PROST). The PROST study evaluated cognitive state and serum vitamin D level from June 2011 to November 2013 for 740 patients (431 men and 309 women). The Mini-Mental State Examination-Japanese version (MMSE-J) and serum 25(OH)D level measurements were used as assessment tools. Cognitive impairment was defined using MMSE-J ≤ 23 as a cutoff. Multiple logistic regression analyses were performed to calculate the odds ratios (ORs) for low MMSE-J scores. The average subject age was 68.1 years, the average MMSE- J score was 25.9, and the average 25(OH)D level was 24.6 ng/mL. Significant ORs for cognitive impairment were observed for both high age and low serum 25(OH)D. The adjusted OR for the lowest versus highest serum 25(OH)D quartiles was 2.70 (95% confidence interval 1.38-5.28, P = 0.0110). Low serum 25(OH)D levels were independently associated with a higher prevalence of cognitive impairment.

DOI： 10.1007/s00774-018-0934-z

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【神経疾患とトレース・メタル-知っていますか?】鉄 Friedreich失調症と鉄代謝査読

坪口晋太朗, 石原智彦, 小野寺理

Clinical Neuroscience 37 ( 3 ) 308 - 310 2019年3月

Neuropathologic characteristics of patients with progressive suprenuclear palsy who died within four years after the disease onset

Lu Zhang, Yasuko Toyoshima, Akari Takeshima, Hiroshi Shimizu, Itsuro Tomita, Osamu Onodera, Hitoshi Takahashi, Akiyoshi Kakita

BRAIN PATHOLOGY 29 77 - 77 2019年2月

Radiological, immunological, and pathological analysis of ependymal cells in neuromyelitis spectrum disorders

Fumihiro Yanagimura, Etsuji Saji, Takahiro Wakasugi, Yasuko Toyoshima, Akiyoshi Kakita, Hitoshi Takahashi, Osamu Onodera, Izumi Kawachi

BRAIN PATHOLOGY 29 134 - 134 2019年2月

Is the population of Sado Island genetically close to the population of western Japan? 査読国際誌

Kazuharu Misawa, Hiroshi Watanabe, Akio Yokoseki, Minako Wakasugi, Osamu Onodera, Ichiei Narita, Takeshi Momotsu, Kenji Sato, Naoto Endo

Human genome variation 6 26 - 26 2019年

記述言語：英語

To explore the effect of aging, a cohort study is being performed on Sado Island, which is located in the Sea of Japan. Sado Island is close to the eastern coast of Japan, yet its population speaks the western Japanese dialect. Consequently, the genetic background of the population of Sado Island is of interest. Based on Nei's genetic distance, we compared the allele frequencies of people from Sado Island to those of people from Nagahama and Miyagi, which are located in the western and northeastern parts of Honshu, respectively. The results showed that the populations of Miyagi and Nagahama are genetically closer to each other than to the population of Sado Island. Because the Sado and Honshu Islands are isolated by a channel, it is possible that genetic drift occurred within Sado Island, which would explain the uniqueness of the people of this region.

DOI： 10.1038/s41439-019-0058-6

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A patient clinically diagnosed as multiple system atrophy harboring LRRK2 p.G2019S

Shoichiro Ando, Takuya Konno, Tomohiko Ishihara, Hideki Hayashi, Natsumi Saito, Kenya Nishioka, Nobutaka Hattori, Zbigniew K. Wszolek, Osamu Onodera

Clinical Parkinsonism & Related Disorders 1 100 - 101 2019年

Duplication and deletion upstream of LMNB1 in autosomal dominant adult-onset leukodystrophy. 査読国際誌

Naomi Mezaki, Takeshi Miura, Kotaro Ogaki, Makoto Eriguchi, Yuri Mizuno, Kenichi Komatsu, Hiroki Yamazaki, Natsuki Suetsugi, Sumihiro Kawajiri, Ryo Yamasaki, Takanobu Ishiguro, Takuya Konno, Hiroaki Nozaki, Kensaku Kasuga, Yasuyuki Okuma, Jun-Ichi Kira, Hideo Hara, Osamu Onodera, Takeshi Ikeuchi

Neurology. Genetics 4 ( 6 ) e292 2018年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

Objective: To characterize the genetic and clinical features of patients with autosomal dominant adult-onset demyelinating leukodystrophy (ADLD) carrying duplication and deletion upstream of lamin B1 (LMNB1). Methods: Ninety-three patients with adult-onset leukoencephalopathy of unknown etiology were genetically analyzed for copy numbers of LMNB1 and its upstream genes. We examined LMNB1 expression by reverse transcription-qPCR using total RNA extracted from peripheral leukocytes. Clinical and MRI features of the patients with ADLD were retrospectively analyzed. Results: We identified 4 patients from 3 families with LMNB1 duplication. The duplicated genomic regions were different from those previously reported. The mRNA expression level of LMNB1 in patients with duplication was significantly increased. The clinical features of our patients with LMNB1 duplication were similar to those reported previously, except for the high frequency of cognitive impairment in our patients. We found 2 patients from 1 family carrying a 249-kb genomic deletion upstream of LMNB1. Patients with the deletion exhibited relatively earlier onset, more prominent cognitive impairment, and fewer autonomic symptoms than patients with duplication. The presence of cerebellar symptoms and lesions may be characteristic in our patients with the deletion compared with the previously reported family with the deletion. Magnetic resonance images of patients with the deletion exhibited a widespread distribution of white matter lesions including the anterior temporal region. Conclusions: We identified 4 Japanese families with ADLD carrying duplication or deletion upstream of LMNB1. There are differences in clinical and MRI features between the patients with the duplication and those with the deletion upstream of LMNB1.

DOI： 10.1212/NXG.0000000000000292

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本邦におけるCADASILの現状査読

新堂晃大, 田部井賢一, 谷口彰, 小野寺理, 猪原匡史, 水野敏樹, 冨本秀和

臨床神経学 58 ( Suppl. ) S310 - S310 2018年12月

CADM1 is a diagnostic marker in early-stage mycosis fungoides: Multicenter study of 58 cases 査読国際誌

Akihiko Yuki, Satoru Shinkuma, Ryota Hayashi, Hiroki Fujikawa, Taisuke Kato, Erina Homma, Yohei Hamade, Osamu Onodera, Masao Matsuoka, Hiroshi Shimizu, Hiroaki Iwata, Riichiro Abe

JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY 79 ( 6 ) 1039 - 1046 2018年12月

進行性核上性麻痺における臨床型別臨床経過の検討多施設共同前向きコホート研究

饗場郁子, 池内健, 瀧川洋史, 徳田隆彦, 下畑享良, 森田光哉, 村山繁雄, 小野寺理, 長谷川一子, 古和久典, 花島律子, 中島健二, JALPACコンソーシアム

臨床神経学 58 ( Suppl. ) S211 - S211 2018年12月

PSP Rating Scaleによる進行性核上性麻痺の経時的変化に関する検討

瀧川洋史, 池内健, 饗場郁子, 森田光哉, 小野寺理, 下畑享良, 徳田隆彦, 村山繁雄, 長谷川一子, 古和久典, 花島律子, 中島健二, JALPACコンソーシアム

臨床神経学 58 ( Suppl. ) S261 - S261 2018年12月

Clinicopathologic Features of Two Patients With Sporadic Amyotrophic Lateral Sclerosis Who Maintained Communication Ability for Over 30 Years. 査読国際誌

Junko Ito, Tetsuro Shimada, Mari Tada, Hiroshi Shimizu, Masatoshi Wakabayashi, Akio Yokoseki, Osamu Onodera, Hitoshi Takahashi, Akiyoshi Kakita

Journal of neuropathology and experimental neurology 77 ( 11 ) 981 - 986 2018年11月

記述言語：英語

We report the clinicopathologic features of 2 unrelated patients with sporadic amyotrophic lateral sclerosis (SALS) supported by tracheostomy and invasive ventilation (TIV) who were able to maintain communication ability for more than 30 years after disease onset. In both cases, the age at onset was younger than the mean, initially the progression of muscle weakness was consistent with that in the majority of SALS patients, and TIV became necessary several years after disease onset. Thereafter, however, their neurologic deterioration slowed and the patients were able to operate computers by facial movements for several decades. At autopsy, neuronal loss appeared to be confined to the motor neuron system. Furthermore, while Betz cells and lower motor neurons in the spinal anterior horns and hypoglossal nucleus were severely depleted, other pyramidal neurons in the motor cortex, and lower motor neurons in the other brainstem motor nuclei were retained. Neuronal and glial cytoplasmic inclusions immunoreactive for phosphorylated 43-kDa TAR DNA-binding protein (TDP-43) were evident in the CNS, but in extremely small numbers. The present patients may represent a distinct subgroup of patients with SALS who are able to maintain communication ability for an extremely long period, accompanied by very mild TDP-43 pathology.

DOI： 10.1093/jnen/nly082

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Identification and functional characterization of novel mutations including frameshift mutation in exon 4 of CSF1R in patients with adult-onset leukoencephalopathy with axonal spheroids and pigmented glia. 査読国際誌

Takeshi Miura, Naomi Mezaki, Takuya Konno, Akio Iwasaki, Naoyuki Hara, Masatomo Miura, Michitaka Funayama, Yuki Unai, Yuichi Tashiro, Kenji Okita, Takeshi Kihara, Nobuo Ito, Yoichi Kanatsuka, David T Jones, Norikazu Hara, Takanobu Ishiguro, Takayoshi Tokutake, Kensaku Kasuga, Hiroaki Nozaki, Dennis W Dickson, Osamu Onodera, Zbigniew K Wszolek, Takeshi Ikeuchi

Journal of neurology 265 ( 10 ) 2415 - 2424 2018年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVE: Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is caused by mutations in CSF1R. Pathogenic mutations in exons 12-22 including coding sequence of the tyrosine kinase domain (TKD) of CSF1R were previously identified. We aimed to identify CSF1R mutations in patients who were clinically suspected of having ALSP and to determine the pathogenicity of novel CSF1R variants. METHODS: Sixty-one patients who fulfilled the diagnostic criteria of ALSP were included in this study. Genetic analysis of CSF1R was performed for all the coding exons. The haploinsufficiency of CSF1R was examined for frameshift mutations by RT-PCR. Ligand-dependent autophosphorylation of CSF1R was examined in cells expressing CSF1R mutants. RESULTS: We identified ten variants in CSF1R including two novel frameshift, five novel missense, and two known missense mutations as well as one known missense variant. Eight mutations were located in TKD. One frameshift mutation (p.Pro104LeufsTer8) and one missense variant (p.His362Arg) were located in the extracellular domain. RT-PCR analysis revealed that the frameshift mutation of p.Pro104LeufsTer8 caused nonsense-mediated mRNA decay. Functional assay revealed that none of the mutations within TKD showed autophosphorylation of CSF1R. The p.His362Arg variant located in the extracellular domain showed comparable autophosphorylation of CSF1R to the wild type, suggesting that this variant is not likely pathogenic. CONCLUSIONS: The detection of the CSF1R mutation outside of the region-encoding TKD may extend the genetic spectrum of ALSP with CSF1R mutations. Mutational analysis of all the coding exons of CSF1R should be considered for patients clinically suspected of having ALSP.

DOI： 10.1007/s00415-018-9017-2

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ショウジョウバエモデルによるC9-ALS/FTDの病態解明

上山盛夫, 石黒太郎, Gendron Tania F, 今野卓哉, 小山哲秀, 望月秀樹, 和田圭司, 石川欣也, 小野寺理, 永井義隆

Dementia Japan 32 ( 3 ) 435 - 435 2018年9月

Histopathologic features of an autopsied patient with cerebral small vessel disease and a heterozygous HTRA1 mutation. 査読国際誌

Junko Ito, Hiroaki Nozaki, Yasuko Toyoshima, Takashi Abe, Aki Sato, Hideki Hashidate, Shuichi Igarashi, Osamu Onodera, Hitoshi Takahashi, Akiyoshi Kakita

Neuropathology : official journal of the Japanese Society of Neuropathology 2018年5月

記述言語：英語

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a hereditary cerebral small vessel disease (CSVD) caused by homozygous or compound heterozygous mutations of the high temperature requirement A serine peptidase 1 gene (HTRA1). Affected patients suffer from cognitive impairment, recurrent strokes, lumbago and alopecia. Recently, clinical studies have indicated that some patients with heterozygous mutations in HTRA1 may also suffer CSVD. Here, we report the histopathologic features of an autopsied 55-year-old male patient who had shown cognitive impairment and multiple cerebral infarcts, and was found to have a heterozygous missense mutation (p.R302Q) in the HTRA1 gene. Histologically, small vessels in the brain and spinal cord showed intimal proliferation, splitting of the internal elastic lamina, and degeneration of smooth muscle cells in the tunica media. Thus, although less severe, the features were quite similar to those of patients with CARASIL, indicating that patients with heterozygous mutations develop CSVD through underlying pathomechanisms similar to those of CARASIL.

DOI： 10.1111/neup.12473

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Predictors of cognitive impairment in multiple system atrophy. 査読国際誌

Masahiro Hatakeyama, Tomoe Sato, Tetsuya Takahashi, Masato Kanazawa, Osamu Onodera, Masatoyo Nishizawa, Takayoshi Shimohata

Journal of the neurological sciences 388 128 - 132 2018年5月

記述言語：英語

OBJECTIVE: To determine predictors of cognitive impairment and frontal dysfunction in patients with multiple system atrophy (MSA). METHODS: We recruited 59 patients with MSA and determined the predictors of a decline in the Mini-Mental State Examination (MMSE) and Frontal Assessment Battery (FAB) scores. RESULTS: The MMSE scores negatively correlated with disease duration, Unified MSA Rating Scale (UMSARS) part 1 and 4 scores, and residual urine volume, and positively correlated with the coefficient of variation of electrocardiographic RR intervals. The FAB scores negatively correlated with the UMSARS part 2 score, periventricular hyperintensity grade, and deep white matter hyperintense signal grade. A significant predictor of rapidly progressive cognitive impairment was a high residual urine volume. CONCLUSIONS: Impairment of global cognitive function correlates with the long-term disease duration, global disability due to the disease, and autonomic dysfunction, whereas frontal dysfunction correlates with motor function and degeneration of cerebral white matter.

DOI： 10.1016/j.jns.2018.03.017

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Loss of Motor Neurons Innervating Cervical Muscles in Patients With Multiple System Atrophy and Dropped Head. 査読国際誌

Rie Saito, Mari Tada, Yasuko Toyoshima, Masatoyo Nishizawa, Osamu Onodera, Hitoshi Takahashi, Akiyoshi Kakita

Journal of neuropathology and experimental neurology 77 ( 4 ) 317 - 324 2018年4月

記述言語：英語

We investigated whether loss of motor neurons innervating the neck muscles contributes to dropped head (DH) in multiple system atrophy (MSA). From 75 patients with autopsy-proven MSA, we retrieved 3 who had DH (MSA-DH), and examined the 4th cervical cord segments. Neurons of the medial and lateral nuclear groups (MNG and LNG) innervate the neck and shoulder muscles, respectively. We measured the area of individual neurons in the MNG and LNG, and created an area-frequency histogram. Neurons were classified as large or small based on their area, and their total numbers in the MNG and LNG were counted. In the MNG, the numbers of both total neurons and large neurons were significantly lower in MSA patients than in the controls (214.2 ± 91.4 vs 521.3 ± 74.8, p = 0.0030, and 26.2 ± 9.1 vs 88.0 ± 34.6, p = 0.020, respectively), and were significantly lower in MSA-DH than in MSA-nonDH (139.7 ± 7.6 vs 288.7 ± 74.6, p = 0.048, and 18.0 ± 4.1 vs 34.3 ± 4.1, p = 0.016, respectively). There were no differences in the LNG neuron counts between the MSA-DH and MSA-nonDH groups. Loss of cervical motor neurons may be responsible for DH in MSA.

DOI： 10.1093/jnen/nly007

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Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy. 査読国際誌

Ishiura H, Doi K, Mitsui J, Yoshimura J, Matsukawa MK, Fujiyama A, Toyoshima Y, Kakita A, Takahashi H, Suzuki Y, Sugano S, Qu W, Ichikawa K, Yurino H, Higasa K, Shibata S, Mitsue A, Tanaka M, Ichikawa Y, Takahashi Y, Date H, Matsukawa T, Kanda J, Nakamoto FK, Higashihara M, Abe K, Koike R, Sasagawa M, Kuroha Y, Hasegawa N, Kanesawa N, Kondo T, Hitomi T, Tada M, Takano H, Saito Y, Sanpei K, Onodera O, Nishizawa M, Nakamura M, Yasuda T, Sakiyama Y, Otsuka M, Ueki A, Kaida KI, Shimizu J, Hanajima R, Hayashi T, Terao Y, Inomata-Terada S, Hamada M, Shirota Y, Kubota A, Ugawa Y, Koh K, Takiyama Y, Ohsawa-Yoshida N, Ishiura S, Yamasaki R, Tamaoka A, Akiyama H, Otsuki T, Sano A, Ikeda A, Goto J, Morishita S, Tsuji S

Nature genetics 50 ( 4 ) 581 - 590 2018年4月

Frequency and characteristics of the TBK1 gene variants in Japanese patients with sporadic amyotrophic lateral sclerosis. 査読国際誌

Genki Tohnai, Ryoichi Nakamura, Jun Sone, Masahiro Nakatochi, Daichi Yokoi, Masahisa Katsuno, Hazuki Watanabe, Hirohisa Watanabe, Mizuki Ito, Yuanzhe Li, Yuishin Izumi, Mitsuya Morita, Akira Taniguchi, Osamu Kano, Masaya Oda, Satoshi Kuwabara, Koji Abe, Ikuko Aiba, Koichi Okamoto, Kouichi Mizoguchi, Kazuko Hasegawa, Masashi Aoki, Nobutaka Hattori, Osamu Onodera, Hiroya Naruse, Jun Mitsui, Yuji Takahashi, Jun Goto, Hiroyuki Ishiura, Shinichi Morishita, Jun Yoshimura, Koichiro Doi, Shoji Tsuji, Kenji Nakashima, Ryuji Kaji, Naoki Atsuta, Gen Sobue

Neurobiology of aging 64 158.e15-158.e19 - 158.e19 2018年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease, and the etiology of sporadic ALS is generally unknown. The TANK-binding kinase 1 (TBK1) gene was identified as an ALS gene contributing to a predisposition toward ALS. To reveal the frequency and characteristics of variants of the TBK1 gene in sporadic ALS patients in Japan, we analyzed the TBK1 gene by exome sequencing in a large Japanese cohort of 713 sporadic ALS patients and 800 controls. We identified known or potentially toxic rare variants of TBK1 gene in 9 patients (1.26%) with sporadic ALS, including 4 novel missense variants (p.V23I, p.H322R, p.R358C, and p.T478I) and 3 loss-of-function variants (p.R357X, p.P378_I379del, and p.T419_G420del). The odds ratio between sporadic ALS patients and controls was 10.2 (p = 0.008, 95% confidence interval = 1.67-62.47). These findings support the contribution of TBK1 to the etiology of sporadic ALS in Japanese patients.

DOI： 10.1016/j.neurobiolaging.2017.12.005

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Case Report: A patient with spinocerebellar ataxia type 31 and sporadic Creutzfeldt-Jakob disease. 査読国際誌

Natsumi Saito, Tomohiko Ishihara, Kensaku Kasuga, Mana Nishida, Takanobu Ishiguro, Hiroaki Nozaki, Takayoshi Shimohata, Osamu Onodera, Masatoyo Nishizawa

Prion 12 ( 2 ) 147 - 149 2018年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

We report a Japanese patient with spinocerebellar ataxia type 31 (SCA31) and sporadic Creutzfeldt-Jakob disease (sCJD). A 52-year-old man developed progressive cognitive impairment after the appearance of cerebellar symptoms. Brain MR diffusion-weighted imaging (DWI) demonstrated a slowly expanding hyperintense lesion in the cerebral cortex. The patient was finally diagnosed as having both SCA31 and sCJD by identification of genetic mutations and by real-time quaking-induced conversion (RT-QUIC) analysis of the cerebrospinal fluid (CSF), respectively. Here, we report the clinical details of this rare combined case, with particular reference to the association between prion protein and the early onset of SCA31.

DOI： 10.1080/19336896.2018.1436926

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Diagnostic criteria for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia due to CSF1R mutation 査読

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

European Journal of Neurology 25 ( 1 ) 142 - 147 2018年1月

Operation of a P300-based brain-computer interface in patients with Duchenne muscular dystrophy 査読国際誌

Kota Utsumi, Kouji Takano, Yoji Okahara, Tetsuo Komori, Osamu Onodera, Kenji Kansaku

SCIENTIFIC REPORTS 8 ( 1 ) 1753 - 1753 2018年1月

CARASIL families from India with 3 novel null mutations in the HTRA1 gene. 査読国際誌

Veeramani Preethish-Kumar, Hiroaki Nozaki, Sarbesh Tiwari, Seena Vengalil, Maya Bhat, Chandrajit Prasad, Osamu Onodera, Masahiro Uemura, Seshagiri Doniparthi, Jitender Saini, Saraswati Nashi, Kiran Polavarapu, Atchayaram Nalini

Neurology 89 ( 23 ) 2392 - 2394 2017年12月

Clinical/scientific notes 査読

Neurology 89 ( 23 ) 2392 - 2394 2017年12月

The SMN gene copy number states in Japanese ALS patients

Ishihara T, Toyoda S, Koyama A, Tada M, Atsuta N, Nakamura R, Tohnai G, Sone J, Izumi Y, Kaji R, Morita M, Taniguchi A, Kakita A, Sobue G, Nishizawa M, Onodera O

JOURNAL OF THE NEUROLOGICAL SCIENCES 381 211-211 2017年10月

Apparent diffusion coefficient reduction might be a predictor of poor outcome in patients with posterior reversible encephalopathy syndrome. 査読国際誌

Itaru Ninomiya, Masato Kanazawa, Yasuhisa Akaiwa, Takayoshi Shimohata, Kouichirou Okamoto, Osamu Onodera, Masatoyo Nishizawa

Journal of the neurological sciences 381 1 - 3 2017年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

It is thought that posterior reversible encephalopathy syndrome (PRES) is both clinically and radiologically reversible. However, its reversible nature has been challenged based on reports of permanent neurological impairments. The factors that predict the development of irreversible neurological impairment are still unclear. In the present study, we investigated clinical manifestations, laboratory findings, and neuroradiological images to identify predictors of functional outcomes in PRES. We investigated 23 PRES patients. Apparent diffusion coefficient (ADC) reduction was observed in 4 patients in the poor outcome group, whereas no patients presented ADC reduction in the favourable outcome group (p<0.01). Further studies are warranted to evaluate the association between ADC reduction and functional outcome after PRES.

DOI： 10.1016/j.jns.2017.08.002

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New diagnostic criteria for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukocencephalopathy in Japan. 査読国際誌

Ikuko Mizuta, Akiko Watanabe-Hosomi, Takashi Koizumi, Mao Mukai, Ai Hamano, Yasuhiro Tomii, Masaki Kondo, Masanori Nakagawa, Hidekazu Tomimoto, Teruyuki Hirano, Makoto Uchino, Osamu Onodera, Toshiki Mizuno

Journal of the neurological sciences 381 62 - 67 2017年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

PURPOSE: Definite diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukocencephalopathy (CADASIL) is mostly done by identification of NOTCH3 mutations. We aimed to develop criteria for selecting patients suspected for CADASIL to undergo genetic testing. SUBJECTS AND METHODS: All subjects were Japanese. We recruited CADASIL patients genetically diagnosed up until 2011 (n=37, Group 1) or after 2011 (n=65, Group 2), 67 young stroke patients (≤55 years old), and 53 NOTCH3-negative CADASIL-like patients. The members of Japanese research committee for hereditary cerebral small vessel disease discussed and generated the new criteria to maximize positive rate in Group 1 CADASIL patients, followed by validation of sensitivity and specificity. RESULTS: In Group 1 CADASIL patients, the ages at onset excluding migraine were distributed widely (37-74 years old) and bimodal (<55 and >55 years old). Frequencies of an autosomal dominant family history and vascular risk factor(s) were 73 and 65%, respectively. From these findings, the panel considered appropriate cut-off values and weighting for each item. In CADASIL Group 1 versus young stroke controls, the sensitivity and specificity of the new criteria were 97.3% and 80.6%, respectively. However, in CADASIL Group 2 versus NOTCH3-negative controls, the sensitivity and specificity were 96.9% and 7.5%, respectively. Forty mutations of NOTCH3 distributed in exons 2-8, 11, 14, 18, 19, and 21 were identified in this study. Ten mutations were unreported ones. CONCLUSION: We propose the new criteria of high sensitivity, which will help physicians to assess the need for genetic testing.

DOI： 10.1016/j.jns.2017.08.009

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Association between dialysis treatment and cognitive decline: A study from the Project in Sado for Total Health (PROST), Japan 査読

Yumi Watanabe, Kaori Kitamura, Kazutoshi Nakamura, Kazuhiro Sanpei, Minako Wakasugi, Akio Yokoseki, Keiko Kabasawa, Osamu Onodera, Takeshi Ikeuchi, Ryozo Kuwano, Takeshi Momotsu, Ichici Narita, Naoto Endo

GERIATRICS & GERONTOLOGY INTERNATIONAL 17 ( 10 ) 1584 - 1587 2017年10月

Evidence that phosphorylated ubiquitin signaling is involved in the etiology of Parkinson's disease 査読

Kahori Shiba-Fukushima, Kei-Ichi Ishikawa, Tsuyoshi Inoshita, Nana Izawa, Masashi Takanashi, Shigeto Sato, Osamu Onodera, Wado Akamatsu, Hideyuki Okano, Yuzuru Imai, Nobutaka Hattori

HUMAN MOLECULAR GENETICS 26 ( 16 ) 3172 - 3185 2017年8月

[Overview of Hereditary Spinocerebellar Ataxias in Japan]. 査読

Masayoshi Tada, Akio Yokoseki, Osamu Onodera

Brain and nerve = Shinkei kenkyu no shinpo 69 ( 8 ) 879 - 890 2017年8月

記述言語：日本語

Hereditary spinocerebellar degenerations (SCD) are a group of neurodegenerative disorders characterized by slowly progressive ataxia associated with non-cerebellar neurological signs and symptoms. In the Japanese population, dominantly inherited SCDs are much more common than recessively inherited or X-linked SCDs. The most common dominantly inherited SCD in Japan, as well as in many other countries, is Machado-Joseph disease, also known as spinocerebellar ataxia type 3 (MJD/SCA3). MJD/SCA3 is frequently accompanied by non-cerebellar symptoms, including progressive external ophthalmoplegia, pyramidal signs, dystonia, rigidity, dysarthria, and distal muscle atrophies. SCA6 and SCA31 represent a pure cerebellar subtype of SCD, occasionally accompanied by non-cerebellar signs. Detailed medical history and neurological examination are important for clinicians to diagnose hereditary SCDs, although genetic testing can help confirm the diagnosis. Despite increasing understanding of the molecular mechanisms underlying these fatal diseases, preventive therapies are currently lacking.

DOI： 10.11477/mf.1416200839

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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

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

【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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Modifiable Factors Associated with Cognitive Impairment in 1,143 Japanese Outpatients: The Project in Sado for Total Health (PROST) 査読

Kaori Kitamura, Yumi Watanabe, Kazutoshi Nakamura, Kazuhiro Sanpei, Minako Wakasugi, Akio Yokoseki, Osamu Onodera, Takeshi Ikeuchi, Ryozo Kuwano, Takeshi Momotsu, Ichiei Narita, Naoto Endo

Dementia and Geriatric Cognitive Disorders Extra 6 ( 2 ) 341 - 349 2016年

Elevated C-Reactive Protein Is Associated with Cognitive Decline in Outpatients of a General Hospital: The Project in Sado for Total Health (PROST) 査読

Yumi Watanabe, Kaori Kitamura, Kazutoshi Nakamura, Kazuhiro Sanpei, Minako Wakasugi, Akio Yokoseki, Osamu Onodera, Takeshi Ikeuchi, Ryozo Kuwano, Takeshi Momotsu, Ichiei Narita, Naoto Endo

DEMENTIA AND GERIATRIC COGNITIVE DISORDERS EXTRA 6 ( 1 ) 10 - 19 2016年

Redefining cerebellar ataxia in degenerative ataxias: lessons from recent research on cerebellar systems 査読

Masayoshi Tada, Masatoyo Nishizawa, Osamu Onodera

JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY 86 ( 8 ) 922 - 928 2015年8月

Variants associated with Gaucher disease in multiple system atrophy 査読

Jun Mitsui, Takashi Matsukawa, Hidenao Sasaki, Ichiro Yabe, Masaaki Matsushima, Alexandra Duerr, Alexis Brice, Hiroshi Takashima, Akio Kikuchi, Masashi Aoki, Hiroyuki Ishiura, Tsutomu Yasuda, Hidetoshi Date, Budrul Ahsan, Atsushi Iwata, Jun Goto, Yaeko Ichikawa, Yasuo Nakahara, Yoshio Momose, Yuji Takahashi, Kenju Hara, Akiyoshi Kakita, Mitsunori Yamada, Hitoshi Takahashi, Osamu Onodera, Masatoyo Nishizawa, Hirohisa Watanabe, Mizuki Ito, Gen Sobue, Kinya Ishikawa, Hidehiro Mizusawa, Kazuaki Kanai, Takamichi Hattori, Satoshi Kuwabara, Kimihito Arai, Shigeru Koyano, Yoshiyuki Kuroiwa, Kazuko Hasegawa, Tatsuhiko Yuasa, Kenichi Yasui, Kenji Nakashima, Hijiri Ito, Yuishin Izumi, Ryuji Kaji, Takeo Kato, Susumu Kusunoki, Yasushi Osaki, Masahiro Horiuchi, Tomoyoshi Kondo, Shigeo Murayama, Nobutaka Hattori, Mitsutoshi Yamamoto, Miho Murata, Wataru Satake, Tatsushi Toda, Alessandro Filla, Thomas Klockgether, Ullrich Wuellner, Garth Nicholson, Sid Gilman, Caroline M. Tanner, Walter A. Kukull, Mathew B. Stern, Virginia M. -Y. Lee, John Q. Trojanowski, Eliezer Masliah, Phillip A. Low, Paola Sandroni, Laurie J. Ozelius, Tatiana Foroud, Shoji Tsuji

ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY 2 ( 4 ) 417 - 426 2015年4月

Conformational disease and rna disease theory in the context of neurodegenerative diseases

Tomohiko, I., Osamu, O.

Neurodegenerative Disorders as Systemic Diseases 2015年

Features of Cerebral Autosomal Recessive Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (vol 45, pg 3447, 2014) 査読

Nozaki

STROKE 45 ( 11 ) E237 - E237 2014年11月

C9ORF72 repeat-associated non-ATG-translated polypeptides are distributed independently of TDP-43 in a Japanese patient with c9ALS 査読

T. Konno, M. Tada, A. Shiga, A. Tsujino, H. Eguchi, M. Masuda-Suzukake, M. Hasegawa, M. Nishizawa, O. Onodera, A. Kakita, H. Takahashi

NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY 40 ( 6 ) 783 - 788 2014年10月

A Mutation of COX6A1 Causes a Recessive Axonal or Mixed Form of Charcot-Marie-Tooth Disease 査読

Gen Tamiya, Satoshi Makino, Makiko Hayashi, Akiko Abe, Chikahiko Numakura, Masao Ueki, Atsushi Tanaka, Chizuru Ito, Kiyotaka Toshimori, Nobuhiro Ogawa, Tomoya Terashima, Hiroshi Maegawa, Daijiro Yanagisawa, Ikuo Tooyama, Masayoshi Tada, Osamu Onodera, Kiyoshi Hayasaka

AMERICAN JOURNAL OF HUMAN GENETICS 95 ( 3 ) 294 - 300 2014年9月

Bunina bodies in motor and non-motor neurons revisited: A pathological study of an ALS patient after long-term survival on a respirator 査読

Tadashi Kimura, Haishan Jiang, Takuya Konno, Makiko Seto, Keisuke Iwanaga, Mitsuhiro Tsujihata, Akira Satoh, Osamu Onodera, Akiyoshi Kakita, Hitoshi Takahashi

NEUROPATHOLOGY 34 ( 4 ) 392 - 397 2014年8月

Progressive myoclonus epilepsy: extraneuronal brown pigment deposition and system neurodegeneration in the brains of Japanese patients with novel SCARB2 mutations 査読

Y. -J. Fu, I. Aida, M. Tada, M. Tada, Y. Toyoshima, S. Takeda, T. Nakajima, H. Naito, M. Nishizawa, O. Onodera, A. Kakita, H. Takahashi

NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY 40 ( 5 ) 551 - 563 2014年8月

A 3-year cohort study of the natural history of spinocerebellar ataxia type 6 in Japan 査読

Kenichi Yasui, Ichiro Yabe, Kunihiro Yoshida, Kazuaki Kanai, Kimihito Arai, Mizuki Ito, Osamu Onodera, Shigeru Koyano, Eiji Isozaki, Setsu Sawai, Yoshiki Adachi, Hidenao Sasaki, Satoshi Kuwabara, Takamichi Hattori, Gen Sobue, Hidehiro Mizusawa, Shoji Tsuji, Masatoyo Nishizawa, Kenji Nakashima

ORPHANET JOURNAL OF RARE DISEASES 9 118 2014年7月

A blinded international study on the reliability of genetic testing for GGGGCC-repeat expansions in C9orf72 reveals marked differences in results among 14 laboratories 査読

Chizuru Akimoto, Alexander E. Volk, Marka van Blitterswijk, Marleen Van den Broeck, Claire S. Leblond, Serge Lumbroso, William Camu, Birgit Neitzel, Osamu Onodera, Wouter van Rheenen, Susana Pinto, Markus Weber, Bradley Smith, Melanie Proven, Kevin Talbot, Pamela Keagle, Alessandra Chesi, Antonia Ratti, Julie van der Zee, Helena Alstermark, Anna Birve, Daniela Calini, Angelica Nordin, Daniela C. Tradowsky, Walter Just, Hussein Daoud, Sabrina Angerbauer, Mariely DeJesus-Hernandez, Takuya Konno, Anjali Lloyd-Jani, Mamede de Carvalho, Kevin Mouzat, John E. Landers, Jan H. Veldink, Vincenzo Silani, Aaron D. Gitler, Christopher E. Shaw, Guy A. Rouleau, Leonard H. van den Berg, Christine Van Broeckhoven, Rosa Rademakers, Peter M. Andersen, Christian Kubisch

JOURNAL OF MEDICAL GENETICS 51 ( 6 ) 419 - 424 2014年6月

Minor splicing pathway is not minor any more: Implications for the pathogenesis of motor neuron diseases 査読

Osamu Onodera, Tomohiko Ishihara, Atsushi Shiga, Yuko Ariizumi, Akio Yokoseki, Masatoyo Nishizawa

NEUROPATHOLOGY 34 ( 1 ) 99 - 107 2014年2月

IP3 receptors in neurodegenerative disorders: Spinocerebellar ataxias and Huntington’s and Alzheimer’s diseases 査読

Masayoshi Tada, Masatoyo Nishizawa, Osamu Onodera

Pathologies of Calcium Channels 579 - 600 2014年1月

Haploinsufficiency of CSF-1R and clinicopathologic characterization in patients with HDLS 査読

Takuya Konno, Masayoshi Tada, Mari Tada, Akihide Koyama, Hiroaki Nozaki, Yasuo Harigaya, Jin Nishimiya, Akiko Matsunaga, Nobuaki Yoshikura, Kenji Ishihara, Musashi Arakawa, Aiko Isami, Kenichi Okazaki, Hideaki Yokoo, Kyoko Itoh, Makoto Yoneda, Mitsuru Kawamura, Takashi Inuzuka, Hitoshi Takahashi, Masatoyo Nishizawa, Osamu Onodera, Akiyoshi Kakita, Takeshi Ikeuchi

NEUROLOGY 82 ( 2 ) 139 - 148 2014年1月

Aberration of the spliceosome in amyotrophic lateral sclerosis 査読

Tomohiko Ishihara, Akiyoshi Kakita, Hitoshi Takahashi, Osamu Onodera, Masatoyo Nishizawa

Clinical Neurology 54 ( 12 ) 1155 - 1157 2014年

Early clinical features of patients with progressive supranuclear palsy with predominant cerebellar ataxia 査読

Masato Kanazawa, Mari Tada, Osamu Onodera, Hitoshi Takahashi, Masatoyo Nishizawa, Takayoshi Shimohata

PARKINSONISM & RELATED DISORDERS 19 ( 12 ) 1149 - 1151 2013年12月

ERBB4 Mutations that Disrupt the Neuregulin-ErbB4 Pathway Cause Amyotrophic Lateral Sclerosis Type 19 査読

Yuji Takahashi, Yoko Fukuda, Jun Yoshimura, Atsushi Toyoda, Kari Kurppa, Hiroyoko Moritoyo, Veronique V. Belzil, Patrick A. Dion, Koichiro Higasa, Koichiro Doi, Hiroyuki Ishiura, Jun Mitsui, Hidetoshi Date, Budrul Ahsan, Takashi Matsukawa, Yaeko Ichikawa, Takashi Moritoyo, Mayumi Ikoma, Tsukasa Hashimoto, Fumiharu Kimura, Shigeo Murayama, Osamu Onodera, Masatoyo Nishizawa, Mari Yoshida, Naoki Atsuta, Gen Sobue, Jennifer A. Fifita, Kelly L. Williams, Ian P. Blair, Garth A. Nicholson, Paloma Gonzalez-Perez, Robert H. Brown, Masahiro Nomoto, Klaus Elenius, Guy A. Rouleau, Asao Fujiyama, Shinichi Morishita, Jun Goto, Shoji Tsuji

AMERICAN JOURNAL OF HUMAN GENETICS 93 ( 5 ) 900 - 905 2013年11月

Patient with insidious hypoactive delirium associated with pregabalin 査読

Naomi Mezaki, Tomohiko Ishihara, Tetsutaro Ozawa, Ryoko Takeuchi, Osamu Onodera, Takayoshi Shimohata, Masatoyo Nishizawa

Neurology and Clinical Neuroscience (Online Early View) 2013年9月

Sporadic ALS with compound heterozygous mutations in the SQSTM1 gene 査読

Hiroshi Shimizu, Yasuko Toyoshima, Atsushi Shiga, Akio Yokoseki, Keiko Arakawa, Yumi Sekine, Takayoshi Shimohata, Takeshi Ikeuchi, Masatoyo Nishizawa, Akiyoshi Kakita, Osamu Onodera, Hitoshi Takahashi

Acta Neuropathologica 126 ( 3 ) 453 - 459 2013年9月

Inhibition of SMG-8, a subunit of SMG-1 kinase, ameliorates nonsense-mediated mRNA decay-exacerbated mutant phenotypes without cytotoxicity 査読

Fusako Usuki, Akio Yamashita, Tadafumi Shiraishi, Atsushi Shiga, Osamu Onodera, Itsuro Higuchi, Shigeo Ohno

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 110 ( 37 ) 15037 - 15042 2013年9月

Mutations in COQ2 in Familial and Sporadic Multiple-System Atrophy 査読

Jun Mitsui, Takashi Matsukawa, Hiroyuki Ishiura, Yoko Fukuda, Yaeko Ichikawa, Hidetoshi Date, Budrul Ahsan, Yasuo Nakahara, Yoshio Momose, Yuji Takahashi, Atsushi Iwata, Jun Goto, Yorihiro Yamamoto, Makiko Komata, Katsuhiko Shirahige, Kenju Hara, Akiyoshi Kakita, Mitsunori Yamada, Hitoshi Takahashi, Osamu Onodera, Masatoyo Nishizawa, Hiroshi Takashima, Ryozo Kuwano, Hirohisa Watanabe, Mizuki Ito, Gen Sobue, Hiroyuki Soma, Ichiro Yabe, Hidenao Sasaki, Masashi Aoki, Kinya Ishikawa, Hidehiro Mizusawa, Kazuaki Kanai, Takamichi Hattori, Satoshi Kuwabara, Kimihito Arai, Shigeru Koyano, Yoshiyuki Kuroiwa, Kazuko Hasegawa, Tatsuhiko Yuasa, Kenichi Yasui, Kenji Nakashima, Hijiri Ito, Yuishin Izumi, Ryuji Kaji, Takeo Kato, Susumu Kusunoki, Yasushi Osaki, Masahiro Horiuchi, Tomoyoshi Kondo, Shigeo Murayama, Nobutaka Hattori, Mitsutoshi Yamamoto, Miho Murata, Wataru Satake, Tatsushi Toda, Alexandra Duerr, Alexis Brice, Alessandro Filla, Thomas Klockgether, Ullrich Wuellner, Garth Nicholson, Sid Gilman, Clifford W. Shults, Caroline M. Tanner, Walter A. Kukull, Virginia M. -Y. Lee, Eliezer Masliah, Phillip A. Low, Paola Sandroni, John Q. Trojanowski, Laurie Ozelius, Tatiana Foroud, Shoji Tsuji

NEW ENGLAND JOURNAL OF MEDICINE 369 ( 3 ) 233 - 244 2013年7月

[Hereditary cerebral small-vessel disease]. 査読

Nozaki H, Nishizawa M, Onodera O

Nihon rinsho. Japanese journal of clinical medicine 71 ( 3 ) 545 - 554 2013年3月

Hereditary Diffuse Leukoencephalopathy with Spheroids (HDLS): Clinical Characteristics and Molecular Analyses of CSF-1R 査読

Konno Takuya, Tada Masayoshi, Koyama Akihide, Tada Mari, Sugai Akihiro, Nozaki Hiroaki, Matsunaga Akiko, Harigaya Yasuo, Nishimiya Jin, Ishihara Kenji, Yoneda Makoto, Kakita Akiyoshi, Takahashi Hitoshi, Kawamura Mitsuru, Onodera Osamu, Nishizawa Masatoyo, Ikeuchi Takeshi

NEUROLOGY 80 2013年2月

Early Clinical Features in Japanese Patients with Pathologically Proven Progressive Supranuclear Palsy with Cerebellar Ataxia 査読

Masato Kanazawa, Takayoshi Shimohata, Mari Tada, Osamu Onodera, Hitoshi Takahashi, Masatoyo Nishizawa

NEUROLOGY 80 2013年2月

Molecular pathogenesis of ALS in TDP43 era 査読

Osamu Onodera

Clinical Neurology 53 ( 11 ) 1077 - 1079 2013年

Japanese amyotrophic lateral sclerosis patients with GGGGCC hexanucleotide repeat expansion in C9ORF72 査読

Takuya Konno, Atsushi Shiga, Akira Tsujino, Akihiro Sugai, Taisuke Kato, Kazuaki Kanai, Akio Yokoseki, Hiroto Eguchi, Satoshi Kuwabara, Masatoyo Nishizawa, Hitoshi Takahashi, Osamu Onodera

Journal of Neurology, Neurosurgery and Psychiatry 84 ( 4 ) 398 - 401 2013年

Alteration of POLDIP3 Splicing Associated with Loss of Function of TDP-43 in Tissues Affected with ALS 査読

Atsushi Shiga, Tomohiko Ishihara, Akinori Miyashita, Misaki Kuwabara, Taisuke Kato, Norihiro Watanabe, Akie Yamahira, Chigusa Kondo, Akio Yokoseki, Masuhiro Takahashi, Ryozo Kuwano, Akiyoshi Kakita, Masatoyo Nishizawa, Hitoshi Takahashi, Osamu Onodera

PLOS ONE 7 ( 8 ) e43120 2012年8月

Primary lateral sclerosis: Upper-motor-predominant amyotrophic lateral sclerosis with frontotemporal lobar degeneration - immunohistochemical and biochemical analyses of TDP-43 査読

Takayuki Kosaka, Yong-Juan Fu, Atsushi Shiga, Haruka Ishidaira, Chun-Feng Tan, Takashi Tani, Ryoko Koike, Osamu Onodera, Masatoyo Nishizawa, Akiyoshi Kakita, Hitoshi Takahashi

NEUROPATHOLOGY 32 ( 4 ) 373 - 384 2012年8月

Prevalence of inositol 1, 4, 5-triphosphate receptor type 1 gene deletion, the mutation for spinocerebellar ataxia type 15, in Japan screened by gene dosage 査読

Masato Obayashi, Kinya Ishikawa, Yuishin Izumi, Makoto Takahashi, Yusuke Niimi, Nozomu Sato, Osamu Onodera, Ryuji Kaji, Masatoyo Nishizawa, Hidehiro Mizusawa

JOURNAL OF HUMAN GENETICS 57 ( 3 ) 202 - 206 2012年3月

Co-occurrence of argyrophilic grain disease in sporadic amyotrophic lateral sclerosis 査読

K. Soma, Y. -J. Fu, K. Wakabayashi, O. Onodera, A. Kakita, H. Takahashi

NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY 38 ( 1 ) 54 - 60 2012年2月

What is ataxia? - Towards developing a new scale for ataxia 査読

Osamu Onodera

Clinical Neurology 52 ( 11 ) 988 - 989 2012年

Difference in MSA Phenotype Distribution Between Populations: Genetics or Environment? 査読

Tetsutaro Ozawa, Tamas Revesz, Dominic Paviour, Andrew J. Lees, Niall Quinn, Mari Tada, Akiyoshi Kakita, Osamu Onodera, Koichi Wakabayashi, Hitoshi Takahashi, Masatoyo Nishizawa, Janice L. Holton

JOURNAL OF PARKINSONS DISEASE 2 ( 1 ) 7 - 18 2012年

[Dementia: progress in diagnosis and treatment; Topics, V. Recent topics; 4. Detection of novel dementia-related genes; 2) Dysregulation of TGF-beta family signaling and hereditary cerebral small vessel disease: insight into molecular pathogenesis of CARASIL]. 査読

Nozaki, H., Nishizawa, M., Onodera, O.

Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine 100 ( 8 ) 2207 - 2213 2011年8月

Neuroaxonal integrity evaluated by MR spectroscopy in a case of CARASIL 査読

Yoshinori Nishimoto, Mamoru Shibata, Osamu Onodera, Norihiro Suzuki

JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY 82 ( 8 ) 860 - 861 2011年8月

Functional characterization of the P1059L mutation in the inositol 1,4,5-trisphosphate receptor type 1 identified in a Japanese SCA15 family 査読

Haruka Yamazaki, Hiroaki Nozaki, Osamu Onodera, Takayuki Michikawa, Masatoyo Nishizawa, Katsuhiko Mikoshiba

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 410 ( 4 ) 754 - 758 2011年7月

What is cerebral small vessel disease? 査読

Osamu Onodera

Clinical Neurology 51 ( 6 ) 399 - 405 2011年6月

Reduced bowel sounds in Parkinson's disease and multiple system atrophy patients 査読

Tetsutaro Ozawa, Etsuji Saji, Ryuji Yajima, Osamu Onodera, Masatoyo Nishizawa

CLINICAL AUTONOMIC RESEARCH 21 ( 3 ) 181 - 184 2011年6月

A NOVEL MUTATION IN THE HTRA1 GENE CAUSES CARASIL WITHOUT ALOPECIA 査読

Y. Nishimoto, M. Shibata, M. Nihonmatsu, H. Nozaki, A. Shiga, A. Shirata, K. Yamane, A. Kosakai, K. Takahashi, M. Nishizawa, O. Onodera, N. Suzuki

NEUROLOGY 76 ( 15 ) 1353 - 1355 2011年4月

Identification of novel SNPs of ABCD1, ABCD2, ABCD3, and ABCD4 genes in patients with X-linked adrenoleukodystrophy (ALD) based on comprehensive resequencing and association studies with ALD phenotypes 査読

Takashi Matsukawa, Muriel Asheuer, Yuji Takahashi, Jun Goto, Yasuyuki Suzuki, Nobuyuki Shimozawa, Hiroki Takano, Osamu Onodera, Masatoyo Nishizawa, Patrick Aubourg, Shoji Tsuji

NEUROGENETICS 12 ( 1 ) 41 - 50 2011年2月

[TGF-β family signaling contributes to human cerebral small vessel disease]. 査読

Onodera O

Rinsho shinkeigaku = Clinical neurology 51 ( 11 ) 943 - 944 2011年

The phenotype spectrum of Japanese multiple system atrophy 査読

T. Ozawa, M. Tada, A. Kakita, O. Onodera, M. Tada, T. Ishihara, T. Morita, T. Shimohata, K. Wakabayashi, H. Takahashi, M. Nishizawa

JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY 81 ( 11 ) 1253 - 1255 2010年11月

[Clinical studies on neurological disorders conducted by research consortia]. 査読

Onodera, O., Nakashima, K.

Rinshō shinkeigaku = Clinical neurology 50 ( 11 ) 925 - 925 2010年11月

認知症研究の新しい視点 TDP-43プロテイノパチーとしてのFTLD/ALS 査読

石原智彦, 有泉優子, 志賀篤, 横関明男, 佐藤達哉, 豊島靖子, 柿田明美, 高橋均, 西澤正豊, 小野寺理

臨床神経学 50 ( 11 ) 1022 - 1024 2010年11月

Involvement of Onuf's nucleus in Machado-Joseph disease: a morphometric and immunohistochemical study 査読

Hiroshi Shimizu, Mitsunori Yamada, Yasuko Toyoshima, Takeshi Ikeuchi, Osamu Onodera, Hitoshi Takahashi

ACTA NEUROPATHOLOGICA 120 ( 4 ) 439 - 448 2010年10月

Neuroblastoma amplified sequence gene is associated with a novel short stature syndrome characterised by optic nerve atrophy and Pelger-Huët anomaly. 査読

Maksimova N, Hara K, Nikolaeva I, Chun-Feng T, Usui T, Takagi M, Nishihira Y, Miyashita A, Fujiwara H, Oyama T, Nogovicina A, Sukhomyasova A, Potapova S, Kuwano R, Takahashi H, Nishizawa M, Onodera O

Journal of medical genetics 47 ( 8 ) 538 - 548 2010年8月

Long-Term Disability and Prognosis in Dentatorubral-Pallidoluysian Atrophy: a Correlation with CAG Repeat Length 査読

Arika Hasegawa, Takeshi Ikeuchi, Ryoko Koike, Nae Matsubara, Miyuki Tsuchiya, Hiroaki Nozaki, Atsushi Homma, Jiro Idezuka, Masatoyo Nishizawa, Osamu Onodera

MOVEMENT DISORDERS 25 ( 11 ) 1694 - 1700 2010年8月

Sporadic four-repeat tauopathy with frontotemporal lobar degeneration, Parkinsonism, and motor neuron disease: a distinct clinicopathological and biochemical disease entity 査読

Yong-Juan Fu, Yasushi Nishihira, Shigetoshi Kuroda, Yasuko Toyoshima, Tomohiko Ishihara, Makoto Shinozaki, Akinori Miyashita, Yue-Shan Piao, Chun-Feng Tan, Takashi Tani, Ryoko Koike, Keisuke Iwanaga, Mitsuhiro Tsujihata, Osamu Onodera, Ryozo Kuwano, Masatoyo Nishizawa, Akiyoshi Kakita, Takeshi Ikeuchi, Hitoshi Takahashi

ACTA NEUROPATHOLOGICA 120 ( 1 ) 21 - 32 2010年7月

Molecular pathogenesis of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy 査読

Atsushi Shiga, Hiroaki Nozaki, Masatoyo Nishizawa, Osamu Onodera

Brain and Nerve 62 ( 6 ) 595 - 599 2010年6月

Differential levels of alpha-synuclein, beta-amyloid42 and tau in CSF between patients with dementia with Lewy bodies and Alzheimer's disease 査読

Kensaku Kasuga, Takayoshi Tokutake, Atsushi Ishikawa, Tsuyoshi Uchiyama, Takahiko Tokuda, Osamu Onodera, Masatoyo Nishizawa, Takeshi Ikeuchi

JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY 81 ( 6 ) 608 - 610 2010年6月

Alzheimer's disease: Report of two autopsy cases with a clinical diagnosis of corticobasal degeneration 査読

Kenichi Okazaki, Yong-Juan Fu, Yasushi Nishihira, Minoru Endo, Takao Fukushima, Takeshi Ikeuchi, Kouichirou Okamoto, Osamu Onodera, Masatoyo Nishizawa, Hitoshi Takahashi

NEUROPATHOLOGY 30 ( 2 ) 140 - 148 2010年4月

Increased TGF-beta Signaling Underlies the Pathogenesis of Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CARASIL) 査読

Hiroaki Nozaki, Atushi Shiga, Hirotoshi Kawata, Kunimasa Arima, Kenju Hara, Toshio Fukutake, Akio Yokoseki, Akihide Koyama, Toshiaki Takahashi, Mari Ikeda, Akira Tanaka, Imaharu Nakano, Shu-ichi Ikeda, Tadashi Yamamoto, Takeshi Ikeuchi, Masatoyo Nishizawa, Shoji Tsuji, Osamu Onodera

NEUROLOGY 74 ( 9 ) A445 - A445 2010年3月

The clinical and pathological spectrum of TDP-43 associated ALS 査読

Osamu Onodera, AMo Yokoseki, Chun-Feng Tan, Tomohiko Ishihara, Yasushi Nishiira, Yasuko Toyoshima, AMyoshi Kakita, Masatoyo Nishizawa, Hitoshi Takahashi

Clinical Neurology 50 ( 11 ) 940 - 942 2010年

Early-Onset Ataxia with Ocular Motor Apraxia and Hypoalbuminemia/Ataxia with Oculomotor Apraxia 1 査読

Masayoshi Tada, Akio Yokoseki, Tatsuya Sato, Takao Makifuchi, Osamu Onodera

DISEASES OF DNA REPAIR 685 21 - 33 2010年

The implications of TDP-43 mutations in pathogenesis of amyotrophic lateral sclerosis 査読

Tomohiko Ishihara, Akio Yokoseki, Masatoyo Nishizawa, Hitoshi Takahashi, Osamu Onodera

Brain and Nerve 61 ( 11 ) 1301 - 1307 2009年11月

Selective occurrence of TDP-43-immunoreactive inclusions in the lower motor neurons in Machado-Joseph disease 査読

Chun-Feng Tan, Mitsunori Yamada, Yasuko Toyoshima, Akio Yokoseki, Yukari Miki, Yasuhiro Hoshi, Hiroyuki Kaneko, Takeshi Ikeuchi, Osamu Onodera, Akiyoshi Kakita, Hitoshi Takahashi

ACTA NEUROPATHOLOGICA 118 ( 4 ) 553 - 560 2009年10月

Identification of independent APP locus duplication in Japanese patients with early-onset Alzheimer disease 査読

K. Kasuga, T. Shimohata, A. Nishimura, A. Shiga, T. Mizuguchi, J. Tokunaga, T. Ohno, A. Miyashita, R. Kuwano, N. Matsumoto, O. Onodera, M. Nishizawa, T. Ikeuchi

JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY 80 ( 9 ) 1050 - 1052 2009年9月

Depression and psychiatric symptoms preceding onset of dementia in a family with early-onset Alzheimer disease with a novel PSEN1 mutation 査読

Kensaku Kasuga, Tsukasa Ohno, Tomohiko Ishihara, Akinori Miyashita, Ryozo Kuwano, Osamu Onodera, Masatoyo Nishizawa, Takeshi Ikeuchi

JOURNAL OF NEUROLOGY 256 ( 8 ) 1351 - 1353 2009年8月

Novel GFAP Mutation in Patient with Adult-Onset Alexander Disease Presenting with Spastic Ataxia 査読

Hiroyuki Kaneko, Masaki Hirose, Shinichi Katada, Toshiaki Takahashi, Satoshi Naruse, Miyuki Tsuchiya, Tomokatsu Yoshida, Masanori Nakagawa, Osamu Onodera, Masatoyo Nishizawa, Takeshi Ikeuchi

MOVEMENT DISORDERS 24 ( 9 ) 1393 - 1395 2009年7月

Depletion of medullary serotonergic neurons in patients with multiple system atrophy who succumbed to sudden death 査読

Mari Tada, Akiyoshi Kakita, Yasuko Toyoshima, Osamu Onodera, Tetsutaro Ozawa, Takashi Morita, Masatoyo Nishizawa, Hitoshi Takahashi

BRAIN 132 ( Pt 7 ) 1810 - 1819 2009年7月

Reliability of the Japanese version of the scale for the assessment and rating of ataxia (SARA) 査読

Kazunori Sato, Ichiro Yabe, Hiroyuki Soma, Kenichi Yasui, Mizuki Ito, Takayoshi Shimohata, Osamu Onodera, Kenji Nakashima, Gen Sobue, Masatoyo Nishizawa, Hidenao Sasaki

Brain and Nerve 61 ( 5 ) 591 - 595 2009年5月

Severe neurological phenotypes of Q129 DRPLA transgenic mice serendipitously created by en masse expansion of CAG repeats in Q76 DRPLA mice 査読

Toshiya Sato, Masami Miura, Mitsunori Yamada, Takayuki Yoshida, Jonathan D. Wood, Ikuru Yazawa, Masao Masuda, Takeo Suzuki, Ryong-Moon Shin, Hau-Jie Yau, Fu-Chin Liu, Takayoshi Shimohata, Osamu Onodera, Christopher A. Ross, Motoya Katsuki, Hitoshi Takahashi, Masanobu Kano, Toshihiko Aosaki, Shoji Tsuji

HUMAN MOLECULAR GENETICS 18 ( 4 ) 723 - 736 2009年2月

A patient with anti-aquaporin 4 antibody who presented with recurrent hypersomnia, reduced orexin (hypocretin) level, and symmetrical hypothalamic lesions 査読

Hiroaki Nozaki, Takayoshi Shimohata, Takashi Kanbayashi, Youhei Sagawa, Shin-ichi Katada, Masahisa Satoh, Osamu Onodera, Keiko Tanaka, Masatoyo Nishizawa

SLEEP MEDICINE 10 ( 2 ) 253 - 255 2009年2月

Sporadic amyotrophic lateral sclerosis of long duration is associated with relatively mild TDP-43 pathology 査読

Nishihira, Y., Tan, C.-F., Hoshi, Y., Iwanaga, K., Yamada, M., Kawachi, I., Tsujihata, M., Hozumi, I., Morita, T., Onodera, O., Nishizawa, M., Kakita, A., Takahashi, H.

Acta Neuropathologica 117 ( 1 ) 45 - 53 2009年1月

Sporadic amyotrophic lateral sclerosis of long duration is associated with relatively mild TDP-43 pathology 査読

Yasushi Nishihira, Chun-Feng Tan, Yasuhiro Hoshi, Keisuke Iwanaga, Megumi Yamada, Izumi Kawachi, Mitsuhiro Tsujihata, Isao Hozumi, Takashi Morita, Osamu Onodera, Masatoyo Nishizawa, Akiyoshi Kakita, Hitoshi Takahashi

ACTA NEUROPATHOLOGICA 117 ( 1 ) 45 - 53 2009年1月

Molecular mechanism for spinocerebellar ataxias 査読

Osamu Onodera

Clinical Neurology 49 ( 11 ) 750 - 752 2009年

Molecular mechanism for spinocerebellar ataxias 査読

Osamu Onodera

Clinical Neurology 49 ( 1 ) 1 - 8 2009年

Electroclinical features of epilepsy in patients with juvenile type dentatorubral-pallidoluysian atrophy 査読

Kiyoshi Egawa, Yukitoshi Takahashi, Yuko Kubota, Hideki Kubota, Yushi Inoue, Takeki Fujiwara, Osamu Onodera

EPILEPSIA 49 ( 12 ) 2041 - 2049 2008年12月

Cardiac sympathetic denervation in Parkinson's disease linked to SNCA duplication 査読

Satoshi Orimo, Toshiki Uchihara, Ayako Nakamura, Fumiaki Mori, Takeshi Ikeuchi, Osamu Onodera, Masatoyo Nishizawa, Atsushi Ishikawa, Akiyoshi Kakita, Koichi Wakabayashi, Hitoshi Takahashi

ACTA NEUROPATHOLOGICA 116 ( 5 ) 575 - 577 2008年11月

Development of a high-throughput microarray-based resequencing system for neurological disorders and its application to molecular genetics of amyotrophic lateral sclerosis 査読

Yuji Takahashi, Naomi Seki, Hiroyuki Ishiura, Jun Mitsui, Takashi Matsukawa, Atsushi Kishino, Osamu Onodera, Masashi Aoki, Nobuyuki Shimozawa, Shigeo Murayama, Yasuto Itoyama, Yasuyuki Suzuki, Gen Sobue, Masatoyo Nishizawa, Jun Goto, Shoji Tsuji

ARCHIVES OF NEUROLOGY 65 ( 10 ) 1326 - 1332 2008年10月

Marinesco-Sjögren syndrome with atrophy of the brain stem tegmentum and dysplastic cytoarchitecture in the cerebral cortex. 査読

Sakai K, Tada M, Yonemochi Y, Nakajima T, Onodera O, Takahashi H, Kakita A

Neuropathology : official journal of the Japanese Society of Neuropathology 28 ( 5 ) 541 - 546 2008年10月

Prevalence and incidence rates of chronic inflammatory demyelinating polyneuropathy in the Japanese population 査読

M. Iijima, H. Koike, N. Hattori, A. Tamakoshi, M. Katsuno, F. Tanaka, M. Yamamoto, K. Arimura, G. Sobue, S. Yagihashi, T. Yamamura, S. Ikeda, M. Nakagawa, S. Kusunoki, K. Inoue, K. Hayasaka, K. Matsumura, Y. Ando, M. Baba, M. Nakazato, H. Yasuda, R. Kaji, O. Onodera, J. Kira, S. Kuwabara, K. Arimura, G. Sobue

Journal of Neurology, Neurosurgery and Psychiatry 79 ( 9 ) 1040 - 1043 2008年9月

Total deletion and a missense mutation of ITPR1 in Japanese SCA15 families 査読

K. Hara, A. Shiga, H. Nozaki, J. Mitsui, Y. Takahashi, H. Ishiguro, H. Yomono, H. Kurisaki, J. Goto, T. Ikeuchi, S. Tsuji, M. Nishizawa, O. Onodera

NEUROLOGY 71 ( 8 ) 547 - 551 2008年8月

Sporadic amyotrophic lateral sclerosis: two pathological patterns shown by analysis of distribution of TDP-43-immunoreactive neuronal and glial cytoplasmic inclusions 査読

Yasushi Nishihira, Chun-Feng Tan, Osamu Onodera, Yasuko Toyoshima, Mitsunori Yamada, Takashi Morita, Masatoyo Nishizawa, Akiyoshi Kakita, Hitoshi Takahashi

ACTA NEUROPATHOLOGICA 116 ( 2 ) 169 - 182 2008年8月

Sporadic ataxias in Japan - a population-based epidemiological study 査読

Shoji Tsuji, Osamu Onodera, Jun Goto, Masatoyo Nishizawa

CEREBELLUM 7 ( 2 ) 189 - 197 2008年6月

Patients homozygous and heterozygous for SNCA duplication in a family with parkinsonism and dementia 査読

Takeshi Ikeuchi, Akiyoshi Kakita, Atsushi Shiga, Kensaku Kasuga, Hiryoyuki Kaneko, Chun-Feng Tan, Jiro Idezuka, Koichi Wakabayashi, Osamu Onodera, Takeshi Iwatsubo, Masatoyo Nishizawa, Hitoshi Takahashi, Atsushi Ishikawa

ARCHIVES OF NEUROLOGY 65 ( 4 ) 514 - 519 2008年4月

The clinical-genealogic and molecular-genetic characteristics of oculopharyngeal muscular dystrophy in the Republic of Sakha (Yakutia) 査読

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Total deletion and a missense mutation of ITPR1 in Japanese SCA15 families 査読

Hiroaki Nozaki, Kenju Hara, Atsushi Shiga, Jun Mitsui, Yuuji Takahashi, Hideaki Ishiguro, Harumi Shimono, Hiroshi Kurisaki, Jun Goto, Takeshi Ikeuchi, Shouji Tsuji, Masatoyo Nishizawa, Osamu Onodera

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Akio Yokoseki, Atsushi Shiga, Chun Feng Tan, Asako Tagawa, Hiroyuki Kaneko, Akihide Koyama, Hiroto Eguchi, Akira Tsujino, Takeshi Ikeuchi, Akiyoshi Kakita, Koichi Okamoto, Masatoyo Nishizawa, Hitoshi Takahashi, Osamu Onodera

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Kensaku Kasuga, Atsushi Shiga, Takayoshi Shimohata, Osamu Onodera, Masatoyo Nishizawa, Takeshi Ikeuchi

NEUROSCIENCE RESEARCH 61 S264 - S264 2008年

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N. Maksimova, K. Hara, A. Miyashia, I. Nikolaeva, A. Shiga, A. Nogovicina, A. Sukhomyasova, V. Argunov, A. Shvedova, T. Ikeuchi, M. Nishizawa, R. Kuwano, O. Onodera

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Enhanced accumulation of phosphorylated alpha-synuclein and elevated beta-amyloid 42/40 ratio caused by expression of the presenilin-1 Delta T440 mutant associated with familial Lewy body disease and variant Alzheimer's disease 査読

Hiroyuki Kaneko, Akiyoshi Kakita, Kensaku Kasuga, Hiroaki Nozaki, Atsushi Ishikawa, Akinori Miyashita, Ryozo Kuwano, Genta Ito, Takeshi Iwatsubo, Hitoshi Takahashi, Masatoyo Nishizawa, Osamu Onodera, Sangram S. Sisodia, Takeshi Ikeuchi

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Novel locus for benign hereditary chorea with adult onset maps to chromosome 8q21.3 q23.3. 査読国際誌

Takayoshi Shimohata, Kenju Hara, Kazuhiro Sanpei, Jin-ichi Nunomura, Tetsuya Maeda, Izumi Kawachi, Masato Kanazawa, Kensaku Kasuga, Akinori Miyashita, Ryozo Kuwano, Koichi Hirota, Shoji Tsuji, Osamu Onodera, Masatoyo Nishizawa, Yoshiaki Honma

Brain : a journal of neurology 130 ( Pt 9 ) 2302 - 9 2007年9月

Novel locus for benign hereditary chorea with adult onset maps to chromosome 8q21.3 q23.3. 査読国際誌

Brain : a journal of neurology 130 ( Pt 9 ) 2302 - 9 2007年9月

記述言語：英語

Autosomal dominant choreas are genetically heterogeneous disorders including Huntington disease (HD), Huntington disease like 1 (HDL1), Huntington disease like 2 (HDL2), dentatorubro-pallidoluysian atrophy (DRPLA), spinocerebellar ataxia type 17 (SCA17) and benign hereditary chorea (BHC). We identified two Japanese families with adult-onset benign chorea without dementia inherited in an autosomal dominant pattern. All affected individuals presented slowly progressive choreic movements in their upper and lower extremities, trunk and head with an age of onset ranging from 40 to 66 (average 54.3), which were markedly improved by haloperidol. The affected individuals also developed reduced muscle tones in their extremities. The findings obtained in the brain CT or MRI studies of nine affected individuals were normal. These clinical features resemble those of the so-called 'senile chorea'. HD, HDL1, HDL2, DRPLA, SCA17 and BHC caused by mutations in the TITF-1 gene were excluded by mutational and linkage analyses. A genome-wide linkage analysis revealed linkage to chromosome 8q21.3-q23.3 with a maximum cumulative two-point log of the odds (LOD) score of 4.74 at D8S1784 (theta = 0.00). Haplotype analysis of both the families defined the candidate region as 21.5 Mb interval flanked by M9267 and D8S1139. We named this adult-onset dominant inherited chorea 'benign hereditary chorea type 2 (BHC2)'.

DOI： 10.1093/brain/awm036

PubMed

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Generation of intracellular domain of insulin receptor tyrosine kinase by gamma-secretase 査読

K. Kasuga, H. Kaneko, M. Nishizawa, O. Onodera, T. Ikeuchi

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 360 ( 1 ) 90 - 96 2007年8月

Sacsin-related ataxia with neither retinal hypermyelination nor spasticity 査読

Kenju Hara, Junsuke Shimbo, Hiroaki Nozaki, Koki Kiku-Awa, Osamu Onodera, Masatoyo Nishizawa

MOVEMENT DISORDERS 22 ( 9 ) 1362 - 1363 2007年7月

Daytime hypoxemia, sleep-disordered breathing, and laryngopharyngeal findings in multiple system atrophy 査読

Takayoshi Shimohata, Hideo Shinoda, Hideaki Nakayama, Tetsutaro Ozawa, Kenshi Terajima, Hirohisa Yoshizawa, Yoko Matsuzawa, Osamu Onodera, Satoshi Naruse, Keiko Tanaka, Sugata Takahashi, Fumitake Gejyo, Masatoyo Nishizawa

ARCHIVES OF NEUROLOGY 64 ( 6 ) 856 - 861 2007年6月

TDP-43 immunoreactivity in neuronal inclusions in familial amyotrophic lateral sclerosis with or without SOD1 gene mutation 査読

Chun-Feng Tan, Hiroto Eguchi, Asako Tagawa, Osamu Onodera, Takuya Iwasaki, Akira Tsujino, Masatoyo Nishizawa, Akiyoshi Kakita, Hitoshi Takahashi

ACTA NEUROPATHOLOGICA 113 ( 5 ) 535 - 542 2007年5月

New mutation in the non-gigantic exon of SACS in Japanese siblings 査読

Yuhei Takado, Kenju Hara, Takayoshi Shimohata, Susumu Tokiguchi, Osamu Onodera, Masatoyo Nishizawa

MOVEMENT DISORDERS 22 ( 5 ) 748 - 749 2007年4月

Multiplex families with multiple system atrophy 査読

Kenju Hara, Yoshio Momose, Susumu Tokiguchi, Mitsuteru Shimohata, Kenshi Terajima, Osamu Onodera, Akiyoshi Kakita, Mitsunori Yamada, Hitoshi Takahashi, Motoyuki Hirasawa, Yoshikuni Mizuno, Katsuhisa Ogata, Jun Goto, Ichiro Kanazawa, Masatoyo Nishizawa, Shoji Tsuji

ARCHIVES OF NEUROLOGY 64 ( 4 ) 545 - 551 2007年4月

Clinical and genetic characterizations of 16q-linked autosomal dominant spinocerebellar ataxia (AD-SCA) and frequency analysis of AD-SCA in the Japanese population 査読

Hiroaki Nozaki, Takeshi Ikeuchi, Akio Kawakami, Akio Kimura, Reiji Koide, Miyuki Tsuchiya, Yuusaku Nakmura, Tatsuro Mutoh, Hiroko Yamamoto, Naoki Nakao, Ko Sahashi, Masatoyo Nishizawa, Osamu Onodera

MOVEMENT DISORDERS 22 ( 6 ) 857 - 862 2007年4月

Botulinum toxin A injections improve apraxia of eyelid opening without overt blepharospasm associated with neurodegenerative diseases 査読

Masato Kanazawa, Takayoshi Shimohata, Masahisa Sato, Osamu Onodera, Keiko Tanaka, Masatoyo Nishizawa

MOVEMENT DISORDERS 22 ( 4 ) 597 - 598 2007年3月

New locus for benign hereditary chorea with adult-onset maps to chromosome 8q22.2-q23.3 査読

Kenju Hara, Takayoshi Shimohata, Sanpei Kazuhiro, Jin-ichi Nunomura, Izumi Kawachi, Masato Kanazawa, Kensaku Kasuga, Akinori Miyashita, Ryozo Kuwano, Koichi Hirota, Shoji Tsuji, Osamu Onodera, Masatoyo Nishizawa, Yoshiaki Honma

NEUROLOGY 68 ( 12 ) A326 - A327 2007年3月

Familial amyotrophic lateral sclerosis: a SOD1-unrelated Japanese family of bulbar type with Bunina bodies and ubiquitin-positive skein-like inclusions in lower motor neurons 査読

Asako Tagawa, Chun-Feng Tan, Koki Kikugawa, Masayuki Fukase, Ryoichi Nakano, Osamu Onodera, Masatoyo Nishizawa, Hitoshi Takahashi

ACTA NEUROPATHOLOGICA 113 ( 2 ) 205 - 211 2007年2月

Novel mutation in EIF2B gene in a case of adult-onset leukoencephalopathy with vanishing white matter 査読

Masaru Matsui, Kotaro Mizutani, Hiroaki Ohtake, Yukio Miki, Koichi Ishizu, Hidenao Fukuyama, Takayoshi Shimohata, Osamu Onodera, Masatoyo Nishizawa, Yoshihiro Takayama, Hiroshi Shibasaki

EUROPEAN NEUROLOGY 57 ( 1 ) 57 - 58 2007年

Spinocerebellar ataxia with ocular motor apraxia and DNA repair 査読

Osamu Onodera

NEUROPATHOLOGY 26 ( 4 ) 361 - 367 2006年8月

Long-terms therapeutic efficacy and safety of low-dose tacrolimus (FK506) for myasthenia gravis 査読

Masayoshi Tada, Takayoshi Shimohata, Mari Tada, Mutsuo Oyake, Shuichi Igarashi, Osamu Onodera, Satoshi Naruse, Keiko Tanaka, Shoji Tsuji, Masatoyo Nishizawa

JOURNAL OF THE NEUROLOGICAL SCIENCES 247 ( 1 ) 17 - 20 2006年8月

New HSN2 mutation in Japanese patient with hereditary sensory and autonomic neuropathy type 2 査読

M Takagi, T Ozawa, K Hara, S Naruse, T Ishihara, J Shimbo, S Igarashi, K Tanaka, O Onodera, M Nishizawa

NEUROLOGY 66 ( 8 ) 1251 - 1252 2006年4月

Oral cyclophosphamide therapy for multifocal fibrosclerosis with hypertrophic intracranial pachymeningitis 査読

Masayoshi Tada, Osamu Onodera, Kenju Hara, Keiko Tanaka, Hitoshi Takahashi, Shoji Tsuji, Masatoyo Nishizawa

Clinical Neurology 46 ( 2 ) 128 - 133 2006年2月

Churg-Strauss syndrome and the leukotriene receptor antagonist pranlukast 査読

J Shimbo, O Onodera, K Tanaka, S Tsuji

CLINICAL RHEUMATOLOGY 24 ( 6 ) 661 - 662 2005年12月

Selective silencing of a mutant transthyretin allele by small interfering RNAs 査読

T Kurosawa, S Igarashi, M Nishizawa, O Onodera

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 337 ( 3 ) 1012 - 1018 2005年11月

DNA repair and neurodegeneration 査読

Osamu Onodera

Clinical Neurology 45 ( 11 ) 979 - 981 2005年11月

Natural history of X-linked adrenoleukodystrophy in Japan 査読

Y Suzuki, Y Takemoto, N Shimozawa, T Imanaka, S Kato, H Furuya, M Kaga, K Kato, N Hashimoto, O Onodera, S Tsuji

BRAIN & DEVELOPMENT 27 ( 5 ) 353 - 357 2005年8月

Age associated axonal features in HNPP with 17p11.2 deletion in Japan 査読

H Koike, M Hirayama, M Yamamoto, H Ito, N Hattori, F Umehara, K Arimura, S Ikeda, Y Ando, M Nakazato, R Kaji, K Hayasaka, M Nakagawa, S Sakoda, K Matsumura, O Onodera, M Baba, H Yasuda, T Saito, J Kira, K Nakashima, N Oka, G Sobue

JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY 76 ( 8 ) 1109 - 1114 2005年8月

A late-onset case of oculopharyngeal muscular dystrophy carrying a (GCG) 8 repeat expansion in the PAPBN1 gene 査読

Takayoshi Tokutake, Takeshi Ikeuchi, Keiko Tanaka, Osamu Onodera, Masatoyo Nishizawa

Clinical Neurology 45 ( 6 ) 437 - 440 2005年6月

Clinical and electrophysiologic correlates of IVIg responsiveness in CIDP 査読

M Iijima, M Yamamoto, M Hirayama, F Tanaka, M Katsuno, K Mori, H Koike, N Hattori, K Arimura, M Nakagawa, H Yoshikawa, K Hayasaka, O Onodera, M Baba, H Yasuda, T Saito, M Nakazato, K Nakashima, J Kira, R Kaji, N Oka, G Sobue

NEUROLOGY 64 ( 8 ) 1471 - 1475 2005年4月

A mutant PSEN1 causes dementia with Lewy bodies and variant Alzheimer's disease 査読

A Ishikawa, YS Piao, A Miyashita, R Kuwano, O Onodera, H Ohtake, M Suzuki, M Nishizawa, H Takahashi

ANNALS OF NEUROLOGY 57 ( 3 ) 429 - 434 2005年3月

Sacsin-related autosomal recessive ataxia without prominent retinal myelinated fibers in Japan 査読

K Hara, O Onodera, M Endo, H Kondo, H Shiota, K Miki, N Tanimoto, T Kimura, M Nishizawa

MOVEMENT DISORDERS 20 ( 3 ) 380 - 382 2005年3月

A pedigree of Charcot-Marie-Tooth disease type 4F (Periaxin mutation) 査読

Mitsuteru Shimohata, Kiyoshi Hirahara, Shuichi Igarashi, Kenju Hara, Kazuki Kijima, Osamu Onodera, Keiko Tanaka, Masatoyo Nishizawa, Shoji Tsuji, Kiyoshi Hayasaka

Clinical Neurology 45 ( 3 ) 221 - 225 2005年3月

Polyglutamine represses cAMP-responsive-element-mediated transcription without aggregate formation 査読

T Takahashi, K Nozaki, S Tsuji, M Nishizawa, O Onodera

NEUROREPORT 16 ( 3 ) 295 - 299 2005年2月

Evaluation of two patients with SCA2 with frontal lobe dysfunction using brain SPECT with three-dimensional stereotactic surface projections (3D-SSP) 査読

Takayoshi Shimohata, Yoko Matsuzawa, Koumei Tanaka, Osamu Onodera, Keiko Tanaka, Masatoyo Nishizawa

Clinical Neurology 45 ( 1 ) 22 - 26 2005年1月

The FHA domain of aprataxin interacts with the C-terminal region of XRCC1 査読

H Date, S Igarashi, Y Sano, T Takahashi, T Takahashi, H Takano, S Tsuji, M Nishizawa, O Onodera

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 325 ( 4 ) 1279 - 1285 2004年12月

Clinical spectrums of SCA 17 depend on length of CAA/CAG repeat units in the TBP gene. 査読

Toyoshima Y, Yamada M, Onodera O, Shimohata M, Inenaga C, Fujita N, Morita M, Tsuji S, Takahashi H

Annals of Neurology 56 163 - 164 2004年12月

beta-Synuclein gene alterations in dementia with Lewy bodies 査読

H Ohtake, P Limprasert, Y Fan, O Onodera, A Kakita, H Takahashi, LT Bonner, DW Tsuang, IVJ Murray, VMY Lee, JQ Trojanowski, A Ishikawa, J Idezuka, M Murata, T Toda, TD Bird, JB Leverenz, S Tsuji, AR La Spada

NEUROLOGY 63 ( 5 ) 805 - 811 2004年9月

Quantitative evaluation of brainstem involvement in multiple system atrophy by diffusion-weighted MR imaging 査読

M Kanazawa, T Shimohata, K Terajima, O Onodera, K Tanaka, S Tsuji, K Okamoto, M Nishizawa

JOURNAL OF NEUROLOGY 251 ( 9 ) 1121 - 1124 2004年9月

Five year follow up of a patient with spinal and bulbar muscular atrophy treated with leuprorelin 査読

T Shimohata, T Kimura, M Nishizawa, O Onodera, S Tsuji

JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY 75 ( 8 ) 1206 - 1207 2004年8月

Adult-onset leukoencephalopathy with vanishing white matter with a missense mutation in EIF2B5 査読

H Ohtake, T Shimohata, K Terajima, T Kimura, R Jo, R Kaseda, O Iizuka, M Takano, Y Akaiwa, H Goto, H Kobayashi, T Sugai, T Muratake, T Hosoki, T Shioiri, K Okamoto, O Onodera, K Tanaka, T Someya, T Nakada, S Tsuji

NEUROLOGY 62 ( 9 ) 1601 - 1603 2004年5月

Disruption of the toxic conformation of the expanded polyglutamine stretch leads to suppression of aggregate formation and cytotoxicity 査読

HA Popiel, Y Nagai, O Onodera, T Inui, N Fujikake, Y Urade, WJ Strittmatter, Burke, JR, A Ichikawa, T Toda

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 317 ( 4 ) 1200 - 1206 2004年5月

Aprataxin, a novel protein that protects against genotoxic stress 査読

N Gueven, OJ Becherel, AW Kijas, P Chen, O Howe, JH Rudolph, R Gatti, H Date, O Onodera, G Taucher-Scholz, MF Lavin

HUMAN MOLECULAR GENETICS 13 ( 10 ) 1081 - 1093 2004年5月

Gene diagnosis of patients with chorea 査読

Takayoshi Shimohata, Osamu Onodera, Yoshiaki Honma, Koichi Hirota, Yasuhito Nunomura, Tetsuya Kimura, Izumi Kawachi, Kazuhiro Sanpei, Masatoyo Nishizawa, Shoji Tsuji

Clinical Neurology 44 ( 3 ) 149 - 153 2004年3月

Aprataxin, the causative protein for EAOH is a nuclear protein with a potential role as a DNA repair protein 査読

Y Sano, H Date, S Igarashi, O Onodera, M Oyake, T Takahashi, S Hayashi, M Morimatsu, H Takahashi, T Makifuchi, N Fukuhara, S Tsuji

ANNALS OF NEUROLOGY 55 ( 2 ) 241 - 249 2004年2月

SCA17 homozygote showing Huntington's disease-like phenotype 査読

Y Toyoshima, M Yamada, O Onodera, M Shimohata, C Inenaga, N Fujita, M Morita, S Tsuji, H Takahashi

ANNALS OF NEUROLOGY 55 ( 2 ) 281 - 286 2004年2月

Spinocerebellar ataxia type 17 repeat in patients with huntington's disease-like and ataxia [1] (multiple letters)

Cellini, E., Forleo, P., Nacmias, B., Tedde, A., Bagnoli, S., Piacentini, S., Sorbi, S., Toyoshima, Y., Yamada, M., Onodera, O., Shimohata, M., Inenaga, C., Fujita, N., Morita, M., Tsuji, S., Takahashi, H.

Annals of Neurology 56 ( 1 ) 2004年

Two Cases of Generalized Tetanus Presenting with Dysphagia as an Initial Symptom 査読

Masato Kanazawa, Hideaki Ishiguro, Osamu Onodera, Kenjiro Yoshikawa, Takashi Koide, Aki Arai, Arika Hasegawa, Ryouichi Nakano, Keiko Tanaka, Masatoyo Nishizawa

Brain and Nerve 55 ( 11 ) 973 - 976 2003年11月

Severe generalized dystonia as a presentation of a patient with aprataxin gene mutation 査読

Y Sekijima, T Hashimoto, O Onodera, H Date, T Okano, K Naito, S Tsuji, S Ikeda

MOVEMENT DISORDERS 18 ( 10 ) 1198 - 1200 2003年10月

[Steroid-pulse therapy in Guillain-Barré syndrome associated with cytomegalovirus infection: a case report]. 査読

Tada M, Onodera O, Kawachi I, Hara K, Sato M, Yoshino H, Asano A, Soma Y, Tsuji S

No to shinkei = Brain and nerve 55 ( 7 ) 615 - 621 2003年7月

Demyelinating and axonal features of Charcot-Marie-Tooth disease with mutations of myelin-related proteins (PMP22, MPZ and Cx32): a clinicopathological study of 205 Japanese patients 査読

N Hattori, M Yamamoto, T Yoshihara, H Koike, M Nakagawa, H Yoshikawa, A Ohnishi, K Hayasaka, O Onodera, M Baba, H Yasuda, T Saito, K Nakashima, J Kira, R Kaji, N Oka, G Sobue

BRAIN 126 ( Pt 1 ) 134 - 151 2003年1月

Current states of molecular diagnosis of neurodegenerative disorders

Onodera, O.

Japanese Journal of Clinical Radiology 48 ( 4 ) 2003年

A study of shock wave interaction with a rotating cylinder

Sun, M., Yada, K., Jagadeesh, G., Onodera, O., Ogawa, T., Takayama, K.

Shock Waves 12 ( 6 ) 2003年

皮質基底核変性症(CBD)と進行性核上性麻痺(PSP)の病理診断基準

若林孝一, 高橋均, 高橋均, 小野寺理, 西澤正豊

臨床神経学 42 ( 11 ) 1155 - 1157 2002年11月

記述言語：日本語出版者・発行元：Societas Neurologica Japonica

TDP-43はRNA代謝に関連する核内蛋白である．その機能低下によるRNA代謝異常が，代表的な成人運動ニューロン疾患である筋萎縮性側索硬化症（Amyotrophic lateral sclerosis; ALS）病態機序の一つとして提唱されている．われわれはALS罹患神経組織において，TDP-43機能低下に由来した，核内小体の一種GEM小体数および機能性RNA蛋白複合体minor spliceosomesの発現低下がみられる事を報告した．同様の現象は小児運動ニューロン疾患である脊髄性筋無力症（spinal muscular atrophy）でもみとめられることから，運動ニューロン疾患における選択的神経変性において重要な役割をはたしている可能性がある．

DOI： 10.5692/clinicalneurol.54.1155

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OXIDATIVE/ENERGY METABOLISM IN NEURODEGENERATIVE DISORDERS 893 192 - 202 1999年

Transgenic mice harboring a full-length human mutant DRPLA gene exhibit age-dependent intergenerational and somatic instabilities of CAG repeats comparable with those in DRPLA patients 査読

Toshiya Sato, Mutsuo Oyake, Kenji Nakamura, Kazuki Nakao, Yoshimitsu Fukusima, Osamu Onodera, Shuichi Igarashi, Hiroki Takano, Koki Kikugawa, Yoshinori Ishida, Takayoshi Shimohata, Reiji Koide, Takeshi Ikeuchi, Hajime Tanaka, Naonobu Futamura, Ryusuke Matsumura, Tetsuya Takayanagi, Fumiaki Tanaka, Gen Sobue, Osamu Komure, Mie Takahashi, Akira Sano, Yaeko Ichikawa, Jun Goto, Ichiro Kanazawa, Motoya Katsuki, Shoji Tsuji

Human Molecular Genetics 8 ( 1 ) 99 - 106 1999年

Stability of converging cylindrical shock waves in a vertical annular co-axial diaphragmless shock tube

Hosseini, S.H.R., Onodera, O., Takayama, K.

Transactions of the Japan Society for Aeronautical and Space Sciences 42 ( 135 ) 1999年

Application of shock wave research to geophysics

Takayama, K., Onodera, O., Saito, T.

Journal of Materials Processing Technology 85 ( 1-3 ) 1999年

Evolution of shock waves and the primary vortex loop discharged from a square cross-sectional tube

Jiang, Z., Onodera, O., Takayama, K.

Shock Waves 9 ( 1 ) 1999年

Efficacy of early plasmapheresis in Bickerstaff's encephalitis 査読

T Ozawa, O Onodera, T Inuzuka, Y Soma, S Tsuji

INTERNAL MEDICINE 37 ( 11 ) 986 - 989 1998年11月

A Japanese family with adrenoleukodystrophy with a codon 291 deletion: A clinical, biochemical, pathological, and genetic report 査読

S Kano, M Watanabe, M Kanai, R Koike, O Onodera, S Tsuji, K Okamoto, M Shoji

JOURNAL OF THE NEUROLOGICAL SCIENCES 158 ( 2 ) 187 - 192 1998年6月

Molecular cloning, structural organization, sequence, chromosomal assignment, and expression of the mouse alpha-N-acetylgalactosaminidase gene 査読

T Herrmann, D Schindler, H Tabe, O Onodera, S Igarashi, A Polack, D Zehnpfennig, S Tsuji

GENE 211 ( 2 ) 205 - 214 1998年5月

Apolipoprotein E epsilon 4 allele and progression of cortical Lewy body pathology in Parkinson's disease 査読

K Wakabayashi, A Kakita, S Hayashi, K Okuizumi, O Onodera, H Tanaka, A Ishikawa, S Tsuji, H Takahashi

ACTA NEUROPATHOLOGICA 95 ( 5 ) 450 - 454 1998年5月

A case of chronic enteroviral meningitis and hydrocephalus associated with Bruton type agammaglobulinemia 査読

Tetsutaro Ozawa, Osamu Onodera, Osamu Iizuka, Yoshinori Tanno, Ikuyo Eguchi, Yoshiaki Soma, Shoji Tsuji

Brain and Nerve 50 ( 2 ) 191 - 196 1998年2月

Pick's disease: selective occurrence of apolipoprotein E-immunoreactive Pick bodies in the limbic system 査読

S Hayashi, K Wakabayashi, K Iwanaga, A Kakita, K Seki, M Tanaka, K Okuizumi, O Onodera, H Tanaka, S Tsuji, H Takahashi

ACTA NEUROPATHOLOGICA 95 ( 1 ) 1 - 4 1998年1月

Inhibition of α-ketoglutarate-and pyruvate dehydrogenase complexes in E. coli by a glutathione S-transferase containing a pathological length poly-Q domain: A possible role of energy deficit in neurological diseases associated with poly-Q expansions? 査読

Cooper AJ, Sheu KF, Burke JR, Onodera O, Strittmatter WJ, Roses AD, Blass JP

Age 21 ( 1 ) 25 - 30 1998年1月

Prevertebral abscesses with a protracted insidious clinical course and subsequent lethal, acute pyogenic meningitis and septic shock 査読

Tetsutaro Ozawa, Osamu Onodera, Akiyoshi Kakita, Kenju Aoki, Keiko Tanaka, Yoshiaki Soma, Hitoshi Takahashi, Shoji Tsuji

Brain and Nerve 50 ( 1 ) 75 - 79 1998年1月

Atrophy of the cerebellum and brainstem in dentatorubral pallidoluysian atrophy - Influence of CAG repeat size on MRI findings 査読

R Koide, O Onodera, T Ikeuchi, R Kondo, H Tanaka, S Tokiguchi, A Tomoda, T Miike, F Isa, H Beppu, N Shimizu, Y Watanabe, Y Horikawa, T Shimohata, K Hirota, A Ishikawa, S Tsuji

NEUROLOGY 49 ( 6 ) 1605 - 1612 1997年12月

Transglutaminase-catalyzed inactivation of glyceraldehyde 3-phosphate dehydrogenase and alpha-ketoglutarate dehydrogenase complex by polyglutamine domains of pathological length 査読

AJL Cooper, KFR Sheu, Burke, JR, O Onodera, WJ Stritmatter, AD Roses, JP Blass

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 94 ( 23 ) 12604 - 12609 1997年11月

Oligomerization of expanded-polyglutamine domain fluorescent fusion proteins in cultured mammalian cells 査読

O Onodera, Burke, JR, SE Miller, S Hester, S Tsuji, AD Roses, WJ Strittmatter

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 238 ( 2 ) 599 - 605 1997年9月

Polyglutamine domains are substrates of tissue transglutaminase: Does transglutaminase play a role in expanded CAG/poly-Q neurodegenerative diseases? 査読

AJL Cooper, KFR Sheu, Burke, JR, O Onodera, WJ Strittmatter, AD Roses, JP Blass

JOURNAL OF NEUROCHEMISTRY 69 ( 1 ) 431 - 434 1997年7月

Molecular cloning of murine homologue dentatorubral-pallidoluysian atrophy (DRPLA) cDNA: Strong conservation of a polymorphic CAG repeat in the murine gene 査読

M Oyake, O Onodera, T Shiroishi, H Takano, Y Takahashi, R Kominami, K Moriwaki, T Ikeuchi, S Igarashi, H Tanaka, S Tsuji

GENOMICS 40 ( 1 ) 205 - 207 1997年2月

Changes in anti-HuD antibody titers in the long-term course in paraneoplastic sensory neuropathy 査読

Y Yagi, T Inuzuka, K Takada, R Nakano, Hozumi, I, H Yoshimoto, O Onodera, K Tanaka, S Sato, M Takahashi

EUROPEAN NEUROLOGY 37 ( 2 ) 122 - 123 1997年

Toxicity of expanded polyglutamine-domain proteins in Escherichia coli 査読

O Onodera, AD Roses, S Tsuji, JM Vance, WJ Strittmatter, Burke, JR

FEBS LETTERS 399 ( 1-2 ) 135 - 139 1996年12月

Lack of association of very low density lipoprotein receptor gene polymorphism with Caucasian Alzheimer's disease 査読

K Okuizumi, O Onodera, K Seki, H Tanaka, Y Namba, K Ikeda, AM Saunders, MA PericakVance, AD Roses, S Tsuji

ANNALS OF NEUROLOGY 40 ( 2 ) 251 - 254 1996年8月

Association study between schizophrenia and dopamine D3 receptor gene polymorphism 査読

T Tanaka, S Igarashi, O Onodera, H Tanaka, M Takahashi, M Maeda, K Kameda, S Tsuji, S Ihda

AMERICAN JOURNAL OF MEDICAL GENETICS 67 ( 4 ) 366 - 368 1996年7月

Non-Mendelian transmission in Dentatorubral-Pallidoluysian atrophy and Machado-Joseph disease: The mutant allele is preferentially transmitted in male meiosis 査読

T Ikeuchi, S Igarashi, Y Takiyama, O Onodera, M Oyake, H Takano, R Koide, H Tanaka, S Tsuji

AMERICAN JOURNAL OF HUMAN GENETICS 58 ( 4 ) 730 - 733 1996年4月

Lack of association between dopamine D2 receptor gene Cys311 variant and schizophrenia 査読

T Tanaka, S Igarashi, O Onodera, H Tanaka, N Fukushima, M Takahashi, K Kameda, S Tsuji, S Ihda

AMERICAN JOURNAL OF MEDICAL GENETICS 67 ( 2 ) 208 - 211 1996年4月

Somatic mosaicism of CAG repeat expansion could be associated with brain shrinkage in DRPLA

Takano, H., Onodera, O., Takahashi, H., Yamada, M., Igarashi, S., Oyakei, M., Ikeuchii, T., Koide, R., Tanaka, H., Iwabuchi, K., Tsuji, S.

Japanese Journal of Human Genetics 41 ( 1 ) 33 - 33 1996年

Molecular cloning of murine homologue cdna for dentatorubral-pallidoluysian atrophy (DRPLA) gene

Oyake, M., Onodera, O., Shiroishi, T., Takano, H., Igarashi, S., Tanaka, H., Moriwaki, K., Tsuji, S.

Japanese Journal of Human Genetics 41 ( 1 ) 91 - 91 1996年

Lack of association between dopamine D4 receptor gene and schizophrenia 査読

T Tanaka, S Igarashi, O Onodera, H Tanaka, K Kameda, K Takahashi, S Tsuji, S Ihda

AMERICAN JOURNAL OF MEDICAL GENETICS 60 ( 6 ) 580 - 582 1995年12月

DENTATORUBRAL-PALLIDOLUYSIAN ATROPHY - CLINICAL-FEATURES ARE CLOSELY-RELATED TO UNSTABLE EXPANSIONS OF TRINUCLEOTIDE (CAG) REPEAT 査読

T IKEUCHI, R KOIDE, H TANAKA, O ONODERA, S IGARASHI, H TAKAHASHI, R KONDO, A ISHIKAWA, A TOMODA, T MIIKE, K SATO, Y IHARA, T HAYABARA, F ISA, H TANABE, S TOKIGUCHI, M HAYASHI, N SHIMIZU, F IKUTA, H NAITO, S TSUJI

ANNALS OF NEUROLOGY 37 ( 6 ) 769 - 775 1995年6月

TRIAL TO ESTABLISH AN ANIMAL-MODEL OF PARANEOPLASTIC CEREBELLAR DEGENERATION WITH ANTI-YO ANTIBODY .1. MOUSE STRAINS BEARING DIFFERENT MHC MOLECULES PRODUCE ANTIBODIES ON IMMUNIZATION WITH RECOMBINANT YO PROTEIN, BUT DO NOT CAUSE PURKINJE-CELL LOSS 査読

M TANAKA, K TANAKA, O ONODERA, S TSUJI

CLINICAL NEUROLOGY AND NEUROSURGERY 97 ( 1 ) 95 - 100 1995年2月

TRIAL TO ESTABLISH AN ANIMAL-MODEL OF PARANEOPLASTIC CEREBELLAR DEGENERATION WITH ANTI-YO ANTIBODY .2. PASSIVE TRANSFER OF MURINE MONONUCLEAR-CELLS ACTIVATED WITH RECOMBINANT YO PROTEIN TO PARANEOPLASTIC CEREBELLAR DEGENERATION LYMPHOCYTES IN SEVERE COMBINED IMMUNODEFICIENCY MICE 査読

K TANAKA, M TANAKA, S IGARASHI, O ONODERA, T MIYATAKE, S TSUJI

CLINICAL NEUROLOGY AND NEUROSURGERY 97 ( 1 ) 101 - 105 1995年2月

DENTATORUBRAL-PALLIDOLUYSIAN ATROPHY (DRPLA) - CLOSE CORRELATION OF CAG REPEAT EXPANSIONS WITH THE WIDE SPECTRUM OF CLINICAL PRESENTATIONS AND PROMINENT ANTICIPATION 査読

T IKEUCHI, O ONODERA, M OYAKE, R KOIDE, H TANAKA, S TSUJI

SEMINARS IN CELL BIOLOGY 6 ( 1 ) 37 - 44 1995年2月

LONG-TERM COURSE OF CHANGE IN ANTI-YO ANTIBODY CONTENT IN PARANEOPLASTIC CEREBELLAR DEGENERATION 査読

K TANAKA, M TANAKA, S IGARASHI, O ONODERA, T NAKAJIMA, M YAMAZAKI, T MIYATAKE, S TSUJI

JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY 58 ( 2 ) 256 - 257 1995年2月

Auditory comprehension in transcortical motor aphasia due to a medial lesions of the left frontal lobe 査読

M. Otsuki, Y. Soma, O. Onodera, S. Tsuji, A. Satoh, N. Yamada

Brain and Nerve 47 ( 11 ) 1081 - 1085 1995年

PARTIAL DELETIONS OF PUTATIVE ADRENOLEUKODYSTROPHY (ALD) GENE IN JAPANESE ALD PATIENTS 査読

R KOIKE, O ONODERA, H TABE, K KANEKO, T MIYATAKE, S IWASAKI, M NAKANO, N SHIZUMA, K IKEGUCHI, M NISHIZAWA, J MOSSER, CO SARDE, S TSUJI

HUMAN MUTATION 6 ( 3 ) 263 - 267 1995年

DENTATORUBRAL-PALLIDOLUYSIAN ATROPHY (DRPLA) - MOLECULAR-BASIS FOR WIDE CLINICAL-FEATURES OF DRPLA 査読

T IKEUCHI, R KOIDE, O ONODERA, H TANAKA, M OYAKE, H TAKANO, S TSUJI

CLINICAL NEUROSCIENCE 3 ( 1 ) 23 - 27 1995年

Paraneoplastic cerebellar degeneration - Characterization of anti-yo antibody and underlying cancer 査読

K. Tanaka, M. Tanaka, O. Onodera, S. Tsuji

Clinical Neurology 35 ( 7 ) 770 - 774 1995年

Trial to establish an animal model of paraneoplastic cerebellar degeneration (PCD) with anti-Yo antibody 2. Passive transfer of murine mononuclear cells activated with recombinant Yo protein to naive SJL or PCD lympphocytes to severe combined immunodefic 査読

Tanaka K, Tanaka M, Igarashi S, Onodera O, Miyatake T, Tsuji S

Clin Neurol Neurosurg 97 101 - 105 1995年

Lack of association between dopamine D4 receptor gene and schizophrenia 査読

T. Tanaka, S. Igarashi, O. Onodera, H. Tanaka, K. Kameda, K. Takahashi, S. Tsuji, S. Ihda

American Journal of Medical Genetics - Neuropsychiatric Genetics 60 ( 6 ) 580 - 582 1995年

PASSIVE TRANSFER AND ACTIVE IMMUNIZATION WITH THE RECOMBINANT LEUCINE-ZIPPER (YO) PROTEIN AS AN ATTEMPT TO ESTABLISH AN ANIMAL-MODEL OF PARANEOPLASTIC CEREBELLAR DEGENERATION 査読

K TANAKA, M TANAKA, O ONODERA, S IGARASHI, T MIYATAKE, S TSUJI

JOURNAL OF THE NEUROLOGICAL SCIENCES 127 ( 2 ) 153 - 158 1994年12月

TRINUCLEOTIDE REPEAT LENGTH AND RATE OF PROGRESSION OF HUNTINGTONS-DISEASE 査読

SN ILLARIOSHKIN, S IGARASHI, O ONODERA, ED MARKOVA, NN NIKOLSKAYA, H TANAKA, TZ CHABRASHWILI, NG INSAROVA, K ENDO, IA IVANOVASMOLENSKAYA, S TSUJI

ANNALS OF NEUROLOGY 36 ( 4 ) 630 - 635 1994年10月

APOE-EPSILON-4 AND EARLY-ONSET ALZHEIMERS 査読

K OKUIZUMI, O ONODERA, H TANAKA, H KOBAYASHI, S TSUJI, H TAKAHASHI, K OYANAGI, K SEKI, M TANAKA, S NARUSE, T MIYATAKE, H MIZUSAWA, KANAZAWA, I

NATURE GENETICS 7 ( 1 ) 10 - 11 1994年5月

The detection of anti-Purkinje cell antibody (anti-Yo antibody) by ELISA using recombinant Yo fusion protein 査読

K. Tanaka, M. Tanaka, O. Onodera, S. Igarashi, S. Tsuji

Brain and Nerve 46 ( 1 ) 47 - 51 1994年

USE OF A RADIATION-REDUCED HYBRID PANEL FOR THE LOCALIZATION OF 7 MARKERS IN THE XQ28 REGION OF THE HUMAN GENOME 査読

A SMAHI, B PETERLIN, O ONODERA, S TSUJI, MC FULCHIGNONILATAUD

ANNALES DE GENETIQUE 37 ( 1 ) 11 - 13 1994年

Correlation between degrees of the CTG repeat expansion and clinical features of myotonic dystrophy 査読

I. Eguchi, R. Koike, O. Onodera, K. Tanaka, H. Kondo, S. Tsuji

Clinical Neurology 34 ( 2 ) 118 - 123 1994年

MRI findings of posterior spinal artery syndrome - Report of a case 査読

K. Okuizumi, M. Wakasugi, O. Onodera, H. Okumura, S. Tsuji

Clinical Neurology 34 ( 11 ) 1116 - 1120 1994年

CHROMOSOMAL LOCALIZATION OF THE EPSILON-1, EPSILON-3, AND ZETA-1 SUBUNIT GENES OF THE HUMAN NMDA RECEPTOR-CHANNEL 査読

H TAKANO, O ONODERA, H TANAKA, H MORI, K SAKIMURA, T HORI, H KOBAYASHI, M MISHINA, S TSUJI

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 197 ( 2 ) 922 - 926 1993年12月

ABSENCE OF LINKAGE DISEQUILIBRIUM AT AMYLOID PRECURSOR PROTEIN GENE LOCUS IN JAPANESE FAMILIAL ALZHEIMERS-DISEASE WITH 717VAL-]ILE MUTATION 査読

H TANAKA, S NARUSE, K SEKI, O ONODERA, H KOBAYASHI, T MIYATAKE, A SHIBATA, Y SAKAKI, K KAMINO, T MIKI, N NUKINA, M IMAGAWA, NAKANO, I, T SHIMIZU, T KOJIMA, J HARDY, S TSUJI

NEUROSCIENCE LETTERS 162 ( 1-2 ) 63 - 66 1993年11月

Positional cloning--current status and future directions 査読

Onodera, O., Tsuji, S.

Nippon rinsho. Japanese journal of clinical medicine 51 ( 9 ) 2225 - 2233 1993年9月

Molecular genetic approach for positional cloning of X-chromosome-linked diseases 査読

Onodera, O., Tanabe, H., Tuji, S., Kaneko, K., Kobayashi, H.

Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme 38 ( 3 ) 354 - 360 1993年2月

HTRA1 Disorder 査読

Osamu Onodera, Hiroaki Nozaki, Toshio Fukutake

1993年

記述言語：英語出版者・発行元：University of Washington, Seattle

CLINICAL CHARACTERISTICS: HTRA1 disorder is a phenotypic spectrum in which some individuals have few to no symptoms and others manifest with the more severe CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy) phenotype. Those who have a heterozygous HTRA1 pathogenic variant may have mild neurologic findings (sometimes identified only on neuroimaging) or mild-to-moderate neurologic signs and symptoms of CARASIL. In this chapter, the term "classic CARASIL" refers to the more severe phenotype associated with biallelic pathogenic variants, and "HTRA1 cerebral small vessel disease" (HTRA1-CSVD) refers to the milder phenotype associated with a heterozygous HTRA1 pathogenic variant. Classic CARASIL is characterized by early-onset changes in the deep white matter of the brain observed on MRI, and associated neurologic findings. The most frequent initial symptom is gait disturbance from spasticity beginning between ages 20 and 40 years. Forty-four percent of affected individuals have stroke-like episodes before age 40 years. Mood changes (apathy and irritability), pseudobulbar palsy, and cognitive dysfunction begin between ages 20 and 50 years. The disease progresses slowly following the onset of neurologic symptoms. Scalp alopecia and acute mid- to lower-back pain (lumbago) before age 30 years are characteristic. The most frequent initial symptom in individuals with HTRA1-CSVD is slowly progressive gait disturbance after age 40 years, which may be followed by the development of mood changes and cognitive dysfunction. A majority of affected individuals have a stroke-like episode after age 40 years. Spondylosis and alopecia are seen in a minority of individuals with HTRA1-CSVD. DIAGNOSIS/TESTING: The diagnosis of HTRA1 disorder is established in a proband by identification of either a heterozygous or biallelic pathogenic variant(s) in HTRA1 on molecular genetic testing. MANAGEMENT: Treatment of manifestations: Consideration of anti-platelet therapy and anti-hypertensive therapy for those with cerebral microbleeds; physical therapy, walking aids, and home adaptations for those with gait disturbance; consideration of medication (baclofen or tizanidine) for spasticity; wig or hairpiece for those with alopecia; standard treatment for spinal spondylosis and mood disorder; supportive care including emotional support and counseling for affected individuals and their families. Surveillance: Follow-up intervals are based on the severity and type of symptoms and the needs of the individuals and their caregivers. Agents/circumstances to avoid: Smoking and a high-salt diet, which may hasten the progression of arteriosclerosis. GENETIC COUNSELING: HTRA1 disorder caused by biallelic pathogenic variants (i.e., the classic CARASIL phenotype) is inherited in an autosomal recessive manner. HTRA1 disorder caused by heterozygous pathogenic variants is inherited in an autosomal dominant manner. Autosomal recessive inheritance. At conception, each sib of an affected individual has a 25% chance of inheriting both HTRA1 pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being heterozygous, and a 25% chance of inheriting neither pathogenic variant and not being at risk for HTRA1 disorder. Autosomal dominant inheritance. Each sib of an affected individual has a 50% risk of inheriting the pathogenic variant from their affected parent. Once the HTRA1 pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for HTRA1 disorder are possible.

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CARASIL 査読

Onodera O, Nozaki H, Fukutake T, Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A

1993年

MRI findings of olivopontocerebellar atrophy and Machado-Joseph disease - Diagnostic value of transverse pontine fibers 査読

J. Idezuka, O. Onodera, T. Yuasa, S. Tsuji, J. Ito

Clinical Neurology 33 ( 3 ) 289 - 293 1993年

Spinocerebellar Ataxia Type 17 査読

Yasuko Toyoshima, Osamu Onodera, Mitsunori Yamada, Shoji Tsuji, Hitoshi Takahashi

1993年

記述言語：英語出版者・発行元：University of Washington, Seattle

CLINICAL CHARACTERISTICS: Spinocerebellar ataxia type 17 (SCA17) is characterized by ataxia, dementia, and involuntary movements, including chorea and dystonia. Psychiatric symptoms, pyramidal signs, and rigidity are common. The age of onset ranges from three to 55 years. Individuals with full-penetrance alleles develop neurologic and/or psychiatric symptoms by age 50 years. Ataxia and psychiatric abnormalities are frequently the initial findings, followed by involuntary movement, parkinsonism, dementia, and pyramidal signs. Brain MRI shows variable atrophy of the cerebrum, brain stem, and cerebellum. The clinical features correlate with the length of the polyglutamine expansion but are not absolutely predictive of the clinical course. DIAGNOSIS/TESTING: The diagnosis of SCA17 is established in a proband by identification of an abnormal CAG/CAA repeat expansion in TBP. Affected individuals usually have more than 41 repeats. The CAA and CAG codons both encode glutamine residues resulting in a pathogenic polyglutamine expansion. MANAGEMENT: Treatment of manifestations: Psychotropic medications for psychiatric problems, antiepileptic drugs for seizures (AEDs); botulinum toxin injections for dystonia; adaptation of the environment to accommodate dementia. Prevention of secondary complications: Side effects of psychotropic medications and AEDs may require total or intermittent discontinuation of the treatment or reduction in dose. Surveillance: Annual or semiannual evaluation by a neurologist or more frequently if symptoms are progressing rapidly. Agents/circumstances to avoid: Sedative/hypnotic agents, such as ethanol or certain medications, may exacerbate incoordination. GENETIC COUNSELING: SCA17 is inherited in an autosomal dominant manner. Offspring of affected individuals are at a 50% risk of inheriting the expanded TBP allele. The age of onset, severity, specific symptoms, and progression of the disease are variable and cannot be precisely predicted by family history or size of expansion. Prenatal testing for pregnancies at increased risk is possible if the diagnosis has been established in an affected family member by molecular genetic testing.

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STRONG CORRELATION BETWEEN THE NUMBER OF CAG REPEATS IN ANDROGEN RECEPTOR GENES AND THE CLINICAL ONSET OF FEATURES OF SPINAL AND BULBAR MUSCULAR-ATROPHY 査読

S IGARASHI, Y TANNO, O ONODERA, M YAMAZAKI, S SATO, A ISHIKAWA, N MIYATANI, M NAGASHIMA, Y ISHIKAWA, K SAHASHI, T IBI, T MIYATAKE, S TSUJI

NEUROLOGY 42 ( 12 ) 2300 - 2302 1992年12月

GENOMIC ORGANIZATION OF A CDNA (QM) DEMONSTRATING AN ALTERED MESSENGER-RNA LEVEL IN NONTUMORIGENIC WILMS MICROCELL HYBRID-CELLS AND ITS LOCALIZATION TO XQ28 査読

K KANEKO, H KOBAYASHI, O ONODERA, T MIYATAKE, S TSUJI

HUMAN MOLECULAR GENETICS 1 ( 7 ) 529 - 533 1992年10月

RAPID DIAGNOSIS OF TUBERCULOUS MENINGITIS BY POLYMERASE CHAIN-REACTION (PCR) 査読

K KANEKO, O ONODERA, T MIYATAKE, S TSUJI

NEUROLOGY 40 ( 10 ) 1617 - 1618 1990年10月

ATRIAL STANDSTILL AFTER TREADMILL EXERCISE TEST AND UNIQUE RESPONSE TO ISOPROTERENOL INFUSION IN RECURRENT POSTEXERCISE SYNCOPE 査読

Y TAMURA, O ONODERA, K KODERA, Y IGARASHI, T MIIDA, Y AIZAWA, T IZUMI, A SHIBATA, S TAKANO

AMERICAN JOURNAL OF CARDIOLOGY 65 ( 7 ) 533 - 535 1990年2月

A case of rigid spine syndrome with rimmed vacuole 査読

O. Onodera, M. Yamazaki, T. Atsumi, T. Miyatake, T. Izumi

Clinical Neurology 30 ( 5 ) 516 - 519 1990年

[Research into actual conditions and preventive care in periodontal disease. Relationship between questionnaire results and periodontal disease in youth]. 査読

Nakashima K, Kurihara C, Kawanaga T, Kurihashi Y, Ohsawa K, Onodera O, Shimoyama M, Watanabe Y, Ikeda K

Nihon Shishubyo Gakkai kaishi 31 ( 4 ) 1220 - 1241 1989年12月

記述言語：日本語出版者・発行元：特定非営利活動法人日本歯周病学会

川越市下の若年者3,886名を対象に,口腔清掃の習慣や歯周疾患に関する自覚症状等についての問診表による意識調査と,プラークの付着,歯石の沈着,歯肉の炎症,う蝕,歯列不正およびプロービングデプスについての口腔内診査を行い,両者の関連性について検討した。1.意識調査の結果,歯磨きの回数については,83.1%の者が毎日複数回歯を磨く等,口腔清掃の習慣は向上してきている。2.歯周疾患に関連する自覚症状については,歯磨き時の出血と答えた者が18.4%で最も高い割合を示した。3.歯周疾患の進行と年齢の関連性については,13歳で最高値を示した。また,歯周疾患が進行するにしたがい,男子の占める割合が高くなった(χ^2-test: α<0.01)。4.口腔内診査の結果,歯磨きの回数の減少と歯周疾患の進行の間には有意な関連性が認められた(χ^2-test: α<0.001)。5.歯磨き時わ出血と歯肉の腫脹の自覚症状と歯周疾患の進行との間に強い関連性が認められた(χ^2-test: α<0.001)。6.プラークの付着,歯石の沈着,う蝕および歯列不正の状態の悪化と歯周疾患の進行との間に関連性が認められた(χ^2-test: α<0.001)。

DOI： 10.2329/perio.31.1220

その他リンク： http://search.jamas.or.jp/link/ui/1991208106

[A method of protection on out-flow of hydroxyapatite]. 査読

Watanabe Y, Kurihara N, Nakashima K, Onodera O, Ousawa K, Mashima T, Kurihashi Y, Miyata T, Ikeda K

Nihon Shishubyo Gakkai kaishi 30 ( 4 ) 1108 - 1115 1988年12月

記述言語：日本語出版者・発行元：特定非営利活動法人日本歯周病学会

コラーゲンをペプシン処理して得られたアテロコラーゲンは,抗原性が少なく生体組織においては細胞成長の足場となり,種々の形状に変えることが出来るなどの特徴を持っている。この報告は,アテロコラーゲンインプラント^[○!R]の1%溶液を歯槽骨欠損部に填塞したハイドロキシアパタイトの初期流出の防止を目的として使用した結果についてである。アテロコラーゲンインプラント^[○!R]は,低温では液状を呈し,37℃付近になるとゲル化する性質を持っている。すなわち,ハイドロキシアパタイト填塞面に滴下してゲル化する性質を利用するのである。実験法は術後1週,2週および4週目に半規格X線写真を撮影し,ハイドロキシアパタイト残存量を画像解析装置を用いて比較する。その結果は,術後4週目でのハイドロキシアパタイト残存量からみて,アテロコラーゲンの滴下群が,ハイドロキシアパタイトの流出を有意(p<0.01)に抑制することがわかった。また,肉眼的所見においても炎症症状の早期消退と創面の閉鎖が早期に起こり治癒する傾向を示した。

[The study of dentifrice containing Phellodendron amurense extract on periodontal disease (II). The clinical effects of dentifrice containing Phellodendron amurense extract and anti-inflammatory agents]. 査読

Sato I, Watanabe Y, Shimojima T, Onodera O, Ohsawa K, Nakajima K, Kurihashi Y, Mashima T, Kusunoki K, Ikeda K

Nihon Shishubyo Gakkai kaishi 30 ( 3 ) 887 - 900 1988年9月

記述言語：日本語出版者・発行元：特定非営利活動法人日本歯周病学会

抗プラスミン作用を有するトラネキサム酸,血流改善作用を有する酢酸トコフェロール,抗炎症,抗アレルギー作用を有するβ-グリチルレチン酸に加えた従来の歯磨剤の歯周疾患予防効果を一層高める目的で,さらに収斂性抗炎症作用を有するオウバクエキスを主成分として配合した歯磨剤(K歯磨剤)の検討をするため,K歯磨剤よりオウバクエキスを除いたアクティブプラセボである歯磨剤(A歯磨剤)を対照に2重盲検法により臨床試験を行った。その結果,両歯磨剤群間にはPMA index及び発赤に有意差が認められ,K歯磨剤に高い改善効果が認められた。また,初回検診値に対する各検診値の平均減少率で比較しても,PMA indexではK歯磨剤群は37.1%,A歯磨剤群は30.4%,発赤ではK歯磨剤群39.6%,A歯磨剤群28.6%で,いずれもK歯磨剤群のほうが高い平均減少率を示した。

DOI： 10.2329/perio.30.887

その他リンク： http://search.jamas.or.jp/link/ui/1990140203

[Preventive and epidemic research in periodontal disease. 1. Study of preventive and epidemic research in periodontal disease in psychopathic patients]. 査読

Ikeda K, Kusunoki K, Osawa K, Kurihashi Y, Onodera O, Kin H, Iwakawa Y, Nishimoto M

Nihon Shishubyo Gakkai kaishi 28 ( 2 ) 654 - 661 1986年6月

記述言語：日本語出版者・発行元：特定非営利活動法人日本歯周病学会

歯周疾患の治療を行うための基礎となる疫学的調査を従来, あまり行なわれていない精神病患者を対象に行い, その患者における歯周疾患の罹患状況, 歯科治療に対する意識調査およびその予防対策などについて精神科医と共に検討してみた。対象は山梨療養所に入院加療中の精神病患者219名で, 歯周疾患の罹患状況は219名全員に, そしてそのうち42名に詳細な口腔内診査, 44名に対して歯科治療に対する意識調査, そしてその中の12名には刷掃指導を行った。その結果, 精神病患者の歯周疾患罹患率は, 一般正常成人に比べて高く, さらに, 歯科治療に対する意識調査では一般正常成人との間に差は認められなかったが, 刷掃指導に対するモチベーションは刷掃の理論づけ (意識的) を行うよりも, 「磨きなさい」と言う動作的な指導から行ったほうが効果的であった。また, 精神病患者に対する刷掃指導は, 精神科領域の治療の一助にもなることが示唆された。

DOI： 10.2329/perio.28.654

その他リンク： http://search.jamas.or.jp/link/ui/1987088506

[Systemic considerations in the improvement of periodontal disease]. 査読

Kusunoki K, Shimojima T, Onodera O, Ohsawa K, Miyake T

Josai Shika Daigaku kiyo. The Bulletin of the Josai Dental University 13 ( 3 ) 592 - 602 1984年

[Study of orthodontic problems in patients with periodontal disease. 2. The malposition of teeth in periodontal disease]. 査読

Kusunoki K, Shimojima T, Onodera O, Yamamoto O, Iwakawa Y, Ikeda K

Josai Shika Daigaku kiyo. The Bulletin of the Josai Dental University 13 ( 1 ) 83 - 92 1984年

[Clinical evaluation of regional myocardial blood flow in patients with hypertrophic cardiomyopathy]. 査読

Sekiguchi H, Fukuhara Y, Koh M, Narita H, Yamanaka T, Fujino Y, Mikuniya A, Onodera O

Journal of cardiography 13 ( 4 ) 1059 1983年12月

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