記述言語：英語  

DOI： 10.1002/acn3.51817

PubMed

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掲載種別：研究論文（学術雑誌）   出版者・発行元：MDPI AG  

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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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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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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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers Media S.A.  

DOI： 10.3389/fneur.2021.756038

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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

PubMed

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記述言語：英語  

DOI： 10.1186/s40478-021-01217-3

PubMed

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記述言語：英語  

DOI： 10.1186/s40478-021-01202-w

PubMed

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記述言語：日本語   出版者・発行元：(一社)日本認知症学会  

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記述言語：日本語   出版者・発行元：(一社)日本認知症学会  

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記述言語：日本語   出版者・発行元：(株)羊土社  

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掲載種別：研究論文（学術雑誌）  

DOI： 10.3389/fnagi.2020.00151

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掲載種別：研究論文（学術雑誌）   出版者・発行元：The Korean Movement Disorder Society  

DOI： 10.14802/jmd.19061

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その他リンク： http://e-jmd.org/journal/view.php?doi=10.14802/jmd.19061

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)日本認知症学会  

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記述言語：日本語   出版者・発行元：(株)中外医学社  

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Societas Neurologica Japonica  

DOI： 10.5692/clinicalneurol.cn-001272

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.prdoa.2019.11.002

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掲載種別：研究論文（学術雑誌）  

DOI： 10.3389/fneur.2019.00693

Scopus

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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：Movement Disorder Society of Japan (MDSJ)  

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Societas Neurologica Japonica  

DOI： 10.5692/clinicalneurol.cn-001188

Scopus

PubMed

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掲載種別：書評論文，書評，文献紹介等  

DOI： 10.3389/fneur.2020.00545

Scopus

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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：Movement Disorder Society of Japan (MDSJ)  

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記述言語：日本語   出版者・発行元：日本神経免疫学会  

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記述言語：日本語   出版者・発行元：日本神経免疫学会  

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