担当区分：筆頭著者   掲載種別：研究論文（学術雑誌）   出版者・発行元：Oxford University Press (OUP)  

DOI： 10.1093/jnen/nlac120

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担当区分：筆頭著者   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  

Abstract

Spinocerebellar ataxia (SCA) type 17-digenic TBP/STUB1 disease (SCA17-DI) has been recently segregated from SCA17, caused by digenic inheritance of two gene mutations – intermediate polyglutamine-encoding CAG/CAA repeat expansions (polyQ) in TBP (TBP_{41 − 49}) and STUB1 heterozygosity – the former being associated with SCA17, and the latter with SCA48 and SCAR16 (autosomal recessive). In SCA17, most patients carry intermediate TBP_{41 − 49} alleles but show incomplete penetrance, and the missing heritability can be explained by a new entity whereby TBP_{41 − 49} requires the STUB1 variant to be symptomatic. The STUB1 gene encodes the chaperone-associated E3 ubiquitin ligase (CHIP) involved in ubiquitin-mediated proteasomal control of protein homeostasis. However, reports of the neuropathology are limited and role of STUB1 mutations in SCA17-DI remain unknown. Here we report the clinicopathologic features of identical twin siblings, one of whom was autopsied and was found to carry an intermediate allele (41 and 38 CAG/CAA repeats) in TBP and a heterozygous missense mutation in STUB1 (p.P243L). These patients developed autosomal recessive Huntington’s disease-like symptoms. Brain MRI showed diffuse atrophy of the cerebellum and T2WI revealed hyperintense lesions in the basal ganglia and periventricular deep white matter. The brain histopathology of the patient shared features characteristic of SCA17, such as degeneration of the cerebellar cortex and caudate nucleus, and presence of 1C2-positive neurons. Here we show that mutant CHIP fails to generate the polyubiquitin chain due to disrupted folding of the entire U box domain, thereby affecting the E3 activity of CHIP. When encountering patients with cerebellar ataxia, especially those with Huntington’s disease-like symptoms, genetic testing for STUB1 as well as TBP should be conducted for diagnosis of SCA17-DI, even in cases of sporadic or autosomal recessive inheritance.

DOI： 10.1186/s40478-022-01486-6

PubMed

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その他リンク： https://link.springer.com/article/10.1186/s40478-022-01486-6/fulltext.html

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

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Intravascular large B-cell lymphoma (IVLBCL) is a subtype of B-cell lymphoma, characterized by lymphoma cell proliferation within small blood vessels. We herein describe a rare case with long spinal cord lesions caused by venous congestive myelopathy associated with IVLBCL. An 81-year-old man presented with paraplegia of the lower limbs and sensory disturbances. Magnetic resonance imaging revealed intramedullary longitudinal T2-hyperintensity lesions in the thoracic cords. The patient died three months after disease onset, and a neuropathological analysis revealed predominantly atypical B-lymphocytes located sparsely in the veins of the spinal cord. IVLBCL should be considered in the differential diagnoses of long spinal cord lesions.

DOI： 10.2169/internalmedicine.6717-20

PubMed

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担当区分：筆頭著者,　責任著者   記述言語：英語  

DOI： 10.1186/s40478-020-01008-2

PubMed

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担当区分：筆頭著者   記述言語：英語  

DOI： 10.1186/s40478-020-00945-2

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s40478-019-0774-7

PubMed

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掲載種別：研究論文（学術雑誌）  

Three-dimensional (3D) imaging based on chemical tissue clearing in the post-mortem human brain is a promising approach for stereoscopic understanding of central nervous system diseases. Especially, delipidation of lipid-rich white matter (WM) is a rate-determining step in human brain clearing by hydrophilic reagents. In this study, we described the rapid delipidation of WM by a 1,2-hexanediol (HxD)-based aqueous solution. HxD delipidation enabled rapid clearing of a formalin-fixed human brain specimen including the WM. Although harsh HxD delipidation was applied to the brain tissue, conventional pathological staining patterns and various types of antigenicity were sufficiently preserved. Furthermore, HxD delipidation was compatible with 3D imaging of fluorescently-labeled tissue samples. HxD delipidation could be useful in future 3D neuropathological diagnosis.

DOI： 10.1016/j.bmcl.2019.05.049

PubMed

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担当区分：筆頭著者   掲載種別：研究論文（学術雑誌）  

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

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We describe a strategy for developing hydrophilic chemical cocktails for tissue delipidation, decoloring, refractive index (RI) matching, and decalcification, based on comprehensive chemical profiling. More than 1,600 chemicals were screened by a high-throughput evaluation system for each chemical process. The chemical profiling revealed important chemical factors: salt-free amine with high octanol/water partition-coefficient (logP) for delipidation, N-alkylimidazole for decoloring, aromatic amide for RI matching, and protonation of phosphate ion for decalcification. The strategic integration of optimal chemical cocktails provided a series of CUBIC (clear, unobstructed brain/body imaging cocktails and computational analysis) protocols, which efficiently clear mouse organs, mouse body including bone, and even large primate and human tissues. The updated CUBIC protocols are scalable and reproducible, and they enable three-dimensional imaging of the mammalian body and large primate and human tissues. This strategy represents a future paradigm for the rational design of hydrophilic clearing cocktails that can be used for large tissues.

DOI： 10.1016/j.celrep.2018.07.056

PubMed

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DOI： 10.1007/s13730-017-0300-3

PubMed

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担当区分：筆頭著者   掲載種別：研究論文（学術雑誌）  

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

PubMed

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担当区分：筆頭著者   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/neup.12236

PubMed

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担当区分：筆頭著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）  

We report on the case of a 77-year-old male with genetically proven spinocerebellar ataxia type 31 (SCA31) who had dystonia. He was referred to our hospital for evaluation following a 6-year history of slowly progressive unsteadiness of his left leg during walking and dysarthria at the age of 62 years old. On the basis of his symptoms, we diagnosed him as spinocerebellar degeneration (SCD), and prescribed taltirelin hydrate. However, his symptoms continued to worsen. He required a cane for walking at the age of 63 years, and a wheelchair at the age of 66 years. He was admitted to our hospital following acute cerebral infarction at the age of 77 years. On examination at admission, right hemiparesis and cerebellar ataxia were detected. And left hallux moved involuntarily toward the top surface of the foot at rest, that is dystonia. The dystonia was not associated with cerebral infarction, because it had been several years with dystonia that he got cerebral infarction. Genetic analysis revealed that this patient harbored a heterozygous SCA31 mutation. Previously there have been no reports of SCA31 associated with dystonia. Our case report support clinical heterogeneity of SCA31, and highlight the importance of considering this type in patients with dystonia and ataxia. Patients with the combination of dystonia and ataxia and a family history of a neurodegenerative disorder should be tested for SCA31.

PubMed

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記述言語：日本語   出版者・発行元：日本脳腫瘍病理学会  

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J-GLOBAL

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記述言語：英語  

Cerebral small vessel disease (cSVD) is a leading cause of stroke and lies at the heart of vascular contributions to dementia. Sporadic cSVD is well-recognized and widely studied, whereas monogenic cSVD is incompletely characterized and understood.

DOI： 10.1111/ene.14222

PubMed

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記述言語：日本語   出版者・発行元：新潟医学会  

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その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J00990&link_issn=&doc_id=20201223020011&doc_link_id=%2Fdg3nigta%2F2019%2Fs13311%2F004%2F0389-0389%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdg3nigta%2F2019%2Fs13311%2F004%2F0389-0389%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

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記述言語：日本語   出版者・発行元：(有)科学評論社  

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記述言語：日本語   出版者・発行元：信州医学会  

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記述言語：日本語   出版者・発行元：信州医学会  

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記述言語：日本語   出版者・発行元：新潟医学会  

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2017&ichushi_jid=J00990&link_issn=&doc_id=20170929080010&doc_link_id=%2Fdg3nigta%2F2017%2Fs13105%2F005%2F0313-0314%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdg3nigta%2F2017%2Fs13105%2F005%2F0313-0314%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：日本語   出版者・発行元：北関東医学会  

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記述言語：日本語   出版者・発行元：信州医学会  

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記述言語：日本語   掲載種別：速報，短報，研究ノート等（学術雑誌）   出版者・発行元：Societas Neurologica Japonica  

DOI： 10.5692/clinicalneurol.cn-000677

Scopus

PubMed

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

症例は77歳男性である。56歳頃から左下肢の引きずりと、構音障害が出現した。症状は緩徐に進行し発症7年で杖歩行、10年で車いすが必要になった。62歳時当院初診、脊髄小脳変性症の診断にて、タルチレリンを開始した。今回、脳梗塞のため入院した。入院時神経学的所見として右不全片麻痺と小脳失調症状に加え左下肢のジストニアをみとめた。遺伝子検査をおこなったところspinocerebellar ataxia type 31(SCA31)に特異性の高い、PLEKHG4遺伝子の1塩基置換(-16C>T)と、SCA31 locusにおいて挿入変異をみとめSCA31と診断した。ジストニアを呈するSCA31の既報告はなく、貴重な症例と考え報告する。(著者抄録)

DOI： 10.5692/clinicalneurol.54.643

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本内科学会  

72歳男。患者は体重減少、全身倦怠感を主訴とした。拡張型心筋症で両心室ペーシングを挿入しており、2005年に発作性心房細動に対してアミオダロンを導入した。しかし、2008年2月から徐々にF-T4の上昇とTSH(thyroid stimulating hormone)の低下がみられ、同年6月の外来で明らかな甲状腺中毒症を認め、精査加療のため入院となった。甲状腺99mTcシンチグラムでは甲状腺機能亢進症は否定的で、アミオダロン内服によってII型のamiodarone-induced-thyrotoxicosis(AIT)、破壊性甲状腺炎型が生じたものと考えられた。そこで、アミオダロンを中止して10日間経過をみたが、甲状腺ホルモンの有意な低下を認めず、プレドニゾロン30mgの内服を開始した。開始後2週間目にはF-T3が正常化し、臨床的にも改善が認められ、更に2ヵ月後にはF-T4が、3ヵ月後にはTSHも正常化した。以上、AITでは早期のもT3低下作用を期待して、ステロイド治療を検討すべきと考えられた。

DOI： 10.2169/naika.98.2589

CiNii Article

CiNii Books

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その他リンク： https://jlc.jst.go.jp/DN/JALC/00338907156?from=CiNii

会議種別：シンポジウム・ワークショップ パネル（公募）  

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会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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会議種別：口頭発表（一般）  

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会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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会議種別：口頭発表（招待・特別）  

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記述言語：英語   会議種別：シンポジウム・ワークショップ パネル（指名）  

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