Papers - Nishimoto, Yoshinori

Distinct patterns of cognitive traits in extreme old age and Alzheimer’s disease

Yoshinori Nishimoto, Takashi Sasaki, Yukiko Abe, Norikazu Hara, Akinori Miyashita, Mika Konishi, Yoko Eguchi, Daisuke Ito, Nobuyoshi Hirose, Masaru Mimura, Japanese Alzheimer’s Disease Neuroimaging Initiative (J-ADNI), Takeshi Ikeuchi, Hideyuki Okano, Yasumichi Arai

Alzheimer's ＆ Dementia 21 ( 4 ) e70155 2025.04

Lead author, Accepted,  ISSN  15525260

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INTRODUCTION: Clinical features of cognitive performance in extreme old age differ from those of pathological cognitive decline in Alzheimer's disease (AD). METHODS: We compared cognitive traits between 638 centenarians aged 100–115 years and 208 and 221 patients with AD from independent facilities. RESULTS: The presence of the apolipoprotein E (APOE) ε4 allele did not affect Mini-Mental State Examination (MMSE) scores in centenarians. Centenarians retained the ability to follow three consecutive commands, associated with their educational background and activities of daily living. Cognitive retention remained unchanged in semi-supercentenarians (aged ≥ 105 years) and supercentenarians (aged ≥110 years). A quantitative genome-wide association study (GWAS) identified two loci associated with maintaining the ability to follow three consecutive commands. DISCUSSION: This is the first study to compare cognitive traits between >600 centenarians and patients with AD. Centenarians attained higher MMSE scores for the phenotype of following three consecutive commands than patients with AD, being useful in clinical practice. Highlights: Cognitive phenotypes in centenarians differ from those in the AD groups Clinical trait to follow consecutive instructions is retained in centenarians but not in AD groups GWAS identified SNPs related to the maintained trait of MMSE in centenarians.

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Multiple lines of evidence for disruption of nuclear lamina and nucleoporins in FUS amyotrophic lateral sclerosis

Okada K., Ito D., Morimoto S., Kato C., Oguma Y., Warita H., Suzuki N., Aoki M., Kuramoto J., Kobayashi R., Shinozaki M., Ikawa M., Nakahara J., Takahashi S., Nishimoto Y., Shibata S., Okano H.

Brain 147 ( 11 ) 3933 - 3948 2024.11

ISSN  00068950

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Advanced pathological and genetic approaches have revealed that mutations in fused in sarcoma/translated in liposarcoma (FUS/TLS), which is pivotal for DNA repair, alternative splicing, translation and RNA transport, cause familial amyotrophic lateral sclerosis (ALS). The generation of suitable animal models for ALS is essential for understanding its pathogenesis and developing therapies. Therefore, we used CRISPR-Cas9 to generate FUS-ALS mutation in the non-classical nuclear localization signal (NLS), H517D (mouse position: H509D) and genome-edited mice. FusWT/H509D mice showed progressive motor impairment (accelerating rotarod and DigiGait system) with age, which was associated with the loss of motor neurons and disruption of the nuclear lamina and nucleoporins and DNA damage in spinal cord motor neurons. We confirmed the validity of our model by showing that nuclear lamina and nucleoporin disruption were observed in lower motor neurons differentiated from patient-derived human induced pluripotent stem cells (hiPSC-LMNs) with FUS-H517D and in the post-mortem spinal cord of patients with ALS. RNA sequence analysis revealed that most nuclear lamina and nucleoporin-linking genes were significantly decreased in FUS-H517D hiPSC-LMNs. This evidence suggests that disruption of the nuclear lamina and nucleoporins is crucial for ALS pathomechanisms. Combined with patient-derived hiPSC-LMNs and autopsy samples, this mouse model might provide a more reliable understanding of ALS pathogenesis and might aid in the development of therapeutic strategies.

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Depressive symptoms and carotid arteriosclerosis in very old people aged 85 years and older: A cross-sectional study by the Kawasaki Aging and Wellbeing Project.

Ryo Shikimoto, Takashi Sasaki, Yukiko Abe, Yoshinori Nishimoto, Takumi Hirata, Masaru Mimura, Yasumichi Arai

Psychiatry and Clinical Neurosciences 78 ( 3 ) 209 - 211 2024

Accepted

Determinants of polydoctoring among multimorbid older adults; a cross-sectional study in an urban area of Japan

Takayuki Ando, Takashi Sasaki, Yukiko Abe, Yoshinori Nishimoto, Takumi Hirata, Junji Haruta, Yasumichi Arai

Journal of General and Family Medicine 25 ( 6 ) 376 - 383 2024

Accepted

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Background: Multimorbidity increases with age, leading to various adverse outcomes, including higher mortality, care dependency, hospitalizations, and healthcare costs. Polydoctoring, managing a patient with multimorbidity by multiple healthcare providers, can be a risk of fragmented care and increased healthcare expenditures. This study aims to identify patient-related factors contributing to polydoctoring in older adults with multimorbidity. Methods: This study is a cross-sectional study using baseline data from the Kawasaki Aging and Wellbeing Project. Participants were residents of Kawasaki City aged 85–89 years, without disability in basic activities of daily living, and being able to visit study site. The regularly visited facilities (RVF) index was employed to quantify polydoctoring. Polydoctoring was defined as having two or more RVFs. Poisson regression analysis was conducted to assess the association between polydoctoring and patient demographics, including types of chronic conditions and socioeconomic factors. Results: A total of, 968 participants with multimorbidity were analyzed. Increased RVF was significantly associated with eye diseases (rate ratio [RR] 1.27, 95% confidence interval [CI] 1.12–1.44), osteoporosis (RR 1.22, 95% CI 1.08–1.38), prostate diseases (RR 1.22, 95% CI 1.07–1.40), and osteoarthritis (RR 1.16, 95% CI 1.05–1.27). No significant correlation was found with educational status or financial hardship. Conclusion: The study indicated that certain chronic conditions are linked to increased polydoctoring among multimorbid older adults in Japan. However, most of those conditions are considered to be within a scope of family medicine/general practice. Training general practitioners to manage these conditions could reduce healthcare costs and the treatment burden, indicating a direction for future healthcare policy and medical education.

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Association of polydoctoring and mortality among persons over 85 years with multimorbidity: a prospective cohort study in Japan

Ando T., Sasaki T., Abe Y., Nishimoto Y., Hirata T., Tajima T., Oguma Y., Haruta J., Arai Y.

BJGP Open 8 ( 3 )  2024

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Background: Polydoctoring can increase the risk of care fragmentation among patients with multimorbidity, but its impact on health outcomes remains unclear. Aim: To determine the effects of polydoctoring, as measured by the regularly visited facilities (RVF) indicator, on patient outcomes among older individuals with multimorbidity. Design & setting: Data from the ongoing prospective cohort study, Kawasaki Aging and Wellbeing Project (KAWP), was utilised in this study. Among the 1026 KAWP participants aged 85–89 years, those with two or more chronic conditions were enrolled in this study. Method: Care fragmentation and polydoctoring was evaluated using the RVF, which is a new indicator that measures the number of medical facilities consistently involved in a patient’s care. Based on RVF, mortality was analysed using the Cox proportional hazards model, with adjustments for age, sex, frailty, and number of comorbidities. Results: A significant reduction in mortality rates was observed in participants with an RVF of ≥3 and 2–4 comorbidities (hazard ratio [HR] 0.43, 95% confidence interval [CI] = 0.18 to 0.99, P value = 0.048). However, no significant difference in mortality based on RVF was observed for those with ≥5 comorbidities. Notably, individuals with ≥5 comorbidities and an RVF of 0 had a significantly higher HR for death (HR 2.68, 95% CI = 1.05 to 6.84, P value = 0.039). Conclusion: In older patients with multimorbidity, polydoctoring may reduce mortality in patients with ≤4 coexisting conditions, but it does not significantly impact mortality in those with ≥5 conditions. These findings provide insights for healthcare decision making in managing older patients with multimorbidity.

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Impact of Amyloid and Tau PET on Changes in Diagnosis and Patient Management

Sho Shimohama, Toshiki Tezuka, Takahata Keisuke, Shogyoku Bun, Hajime Tabuchi, Morinobu Seki, Yuki Momota, Natsumi Suzuki, Ayaka Morimoto, Yu Iwabuchi, Masahito Kubota, Yasuharu Yamamoto, Yasunori Sano, Ryo Shikimoto, Kei Funaki, Yu Mimura, Yoshinori Nishimoto, Ryo Ueda, Masahiro Jinzaki, Jin Nakahara, Masaru Mimura, Daisuke Ito

Neurology (Neurology)  100 ( 3 ) e264 - E274 2023

Accepted,  ISSN  00283878

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Background and Objectives: Previous studies have evaluated the diagnostic effect of amyloid PET in selected research cohorts. However, these studies did not assess the clinical impact of the combination of amyloid and tau PETs. Our objective was to evaluate the association of the combination of 2 PETs with changes in diagnosis, treatment, and management in a memory clinic cohort.Methods: All participants underwent amyloid [18F]florbetaben PET and tau PET using [18F]PI-2620 or [18F]Florzolotau, which are potentially useful for the diagnosis of non-Alzheimer disease (AD) tauopathies. Dementia specialists determined a pre- and post-PET diagnosis that existed in both a clinical syndrome (cognitive normal [CN], mild cognitive impairment [MCI], and dementia) and suspected etiology, with a confidence level. In addition, the dementia specialists determined patient treatment in terms of ancillary investigations and management. Results: Among 126 registered participants, 84.9% completed the study procedures and were included in the analysis (CN [n = 40], MCI [n = 25], AD [n = 20], and non-AD dementia [n = 22]). The etiologic diagnosis changed in 25.0% in the CN, 68.0% in the MCI, and 23.8% with dementia. Overall changes in management between pre- and post-PET occurred in 5.0% of CN, 52.0% of MCI, and 38.1% of dementia. Logistic regression analysis revealed that tau PET has stronger associations with change management than amyloid PET in all participants and dementia groups. Discussion: The combination of amyloid and tau PETs was associated with changes in management and diagnosis of MCI and dementia, and the second-generation tau PET has a strong impact on the changes in diagnosis and management in memory clinics. Classification of Evidence: This study provides Class I evidence that the combination of amyloid and tau PETs was associated with changes in management and diagnosis of MCI and dementia.

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Status and physiological significance of circulating adiponectin in the very old and centenarians: an observational study

Takashi Sasaki, Yoshinori Nishimoto, Takumi Hirata, Yukiko Abe, Nobuyoshi Hirose, Michiyo Takayama, Toru Takebayashi, Hideyuki Okano, and Yasumichi Arai.

eLife  12 2023

Accepted

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Background: High levels of circulating adiponectin are associated with increased insulin sensitivity, low prevalence of diabetes, and low body mass index (BMI); however, high levels of circulating adiponectin are also associated with increased mortality in the 60–70 age group. In this study, we aimed to clarify factors associated with circulating high-molecular-weight (cHMW) adiponectin levels and their association with mortality in the very old (85–89 years of age) and centenarians. Methods: The study included 812 (women: 84.4%) for centenarians and 1498 (women: 51.7%) for the very old. The genomic DNA sequence data were obtained by whole-genome sequencing or DNA microarray-imputation methods. Least Absolute Shrinkage and Selection Operator (LASSO) and multivariate regression analyses were used to evaluate cHMW adiponectin characteristics and associated factors. All-cause mortality was analyzed in three quantile groups of cHMW adiponectin levels using Cox regression. Results: The cHMW adiponectin levels were increased significantly beyond 100 years of age, were negatively associated with diabetes prevalence, and were associated with SNVs in CDH13 (p=2.21 × 10-22) and ADIPOQ (p=5.72 × 10-7). Multivariate regression analysis revealed that genetic variants, BMI, and high-density lipoprotein cholesterol (HDLC) were the main factors associated with cHMW adiponectin levels in the very old, whereas the BMI showed no association in centenarians. The hazard ratios for all-cause mortality in the intermediate and high cHMW adiponectin groups in very old men were significantly higher rather than those for all-cause mortality in the low-level cHMW adiponectin group, even after adjustment with BMI. In contrast, the hazard ratios for all-cause mortality were significantly higher for high cHMW adiponectin groups in very old women, but were not significant after adjustment with BMI. Conclusions: cHMW adiponectin levels increased with age until centenarians, and the contribution of known major factors associated with cHMW adiponectin levels, including BMI and HDLC, varies with age, suggesting that its physiological significance also varies with age in the oldest old. Funding: This study was supported by grants from the Ministry of Health, Welfare, and Labour for the Scientific Research Projects for Longevity; a Grant-in-Aid for Scientific Research (No 21590775, 24590898, 15KT0009, 18H03055, 20K20409, 20K07792, 23H03337) from the Japan Society for the Promotion of Science; Keio University Global Research Institute (KGRI), Kanagawa Institute of Industrial Science and Technology (KISTEC), Japan Science and Technology Agency (JST) Research Complex Program "Tonomachi Research Complex" Wellbeing Research Campus: Creating new values through technological and social innovation (JP15667051), the Program for an Integrated Database of Clinical and Genomic Information from the Japan Agency for Medical Research and Development (No. 16kk0205009h001, 17jm0210051h0001, 19dk0207045h0001); the medical-welfare-food-agriculture collaborative consortium project from the Japan Ministry of Agriculture, Forestry, and Fisheries; and the Biobank Japan Program from the Ministry of Education, Culture, Sports, and Technology.

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Measurement of polydoctoring as a crucial component of fragmentation of care among patients with multimorbidity: Cross-sectional study in Japan

Takayuki Ando, Takashi Sasaki, Yukiko Abe, Yoshinori Nishimoto, Takumi Hirata, Junji Haruta, Yasumichi Arai

Journal of General and Family Medicine 24 ( 6 ) 343 - 349 2023

Accepted

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Background: Care fragmentation, characterized by the uncoordinated involvement of multiple healthcare providers, leads to inefficient and ineffective healthcare, posing a significant challenge in managing patients with multimorbidity. In this context, “polydoctoring,” where patients see multiple specialists, emerges as a crucial aspect of care fragmentation. This study seeks to develop an indicator to assess polydoctoring, which can subsequently enhance the management of multimorbidity. Methods: Baseline survey data from the Kawasaki Aging and Wellbeing Project (KAWP) involving independent community-dwelling older adults aged 85–89 were utilized in this cross-sectional study. Polydoctoring measure was defined as the number of regularly visited facilities (RVFs). The association of RVF with the Fragmentation of Care Index (FCI) and the outcome measures of polypharmacy and ambulatory care costs were examined as indicators of care fragmentation. Results: The analysis comprised 968 participants, with an average of 4.70 comorbid chronic conditions; 65.3% of the participants had two or more RVFs, indicating polydoctoring. A significant correlation between RVF and FCI was observed. Modified Poisson regression analyses revealed associations between higher RVF and increased prevalence ratio of polypharmacy. Likewise, a higher RVF was associated with higher outpatient medical costs. Conclusions: RVF was significantly correlated with FCI, polypharmacy, and higher outpatient medical costs. Unlike complex indices, RVF is simple and intuitively comprehensible. Further research is needed to evaluate the impact of care fragmentation on patient outcomes, considering factors such as RVF thresholds, patient multimorbidity, and social support. Understanding the influence of polydoctoring can enhance care quality and efficiency for patients with multimorbidity.

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Prognostic significance of serum testosterone level in patients with castration-resistant prostate cancer treated with cabazitaxel

Fujiwara S., Kosaka T., Nishimoto Y., Kamisawa K., Watanabe K., Baba Y., Takeda T., Matsumoto K., Oya M.

Prostate (Prostate)  84 ( 1 ) 25 - 31 2023

ISSN  02704137

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Background: Serum testosterone level is a potential prognostic marker for castration-resistant prostate cancer. However, its role as a prognostic marker in cabazitaxel chemotherapy remains unclear. This study aimed to elucidate the clinical significance of serum testosterone levels before cabazitaxel chemotherapy. Methods: This single-institution, retrospective study included 47 patients with metastatic castration-resistant prostate cancer (mCRPC) who received cabazitaxel therapy. Serum testosterone levels were measured before the initiation of cabazitaxel therapy. Results: Progression-free survival and overall survival (OS) were not significantly different between patients with high and low serum testosterone levels. Analysis of patients aged <70 years revealed that those with high serum testosterone levels (total testosterone level > 0.055 ng/mL) had significantly longer OS than those with low serum testosterone levels (total testosterone level < 0.055 ng/mL, p = 0.012). Multivariate analysis revealed that low serum testosterone levels (hazard ratio [HR] = 11.874, 95% confidence interval [CI] 2.076–67.953, p = 0.005) and high prostate-specific antigen levels (HR = 18.051, 95% CI 2.462–132.347, p = 0.004) in the pretreatment phase were independent prognostic factors for OS in patients receiving cabazitaxel therapy. Conclusions: Serum testosterone level may be a prognostic marker for cabazitaxel therapy in patients with mCRPC who are younger than 70 years, and high serum testosterone levels may lead to longer survival.

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“Missing-Piece” Sign with Dural Arteriovenous Fistula at Craniocervical Junction: A Case Report

Toshiki Tezuka, Tomonori Nukariya, Masahiro Katsumata, Tsubasa Miyauchi, Daiki Tokuyasu, Shunpei Azami, Yoshikane Izawa, Narihito Nagoshi, Hirokazu Fujiwara, Katsuhiro Mizutani, Takenori Akiyama, Masahiro Toda, Jin Nakahara, Yoshinori Nishimoto*

Journal of Stroke and Cerebrovascular Diseases (Journal of Stroke and Cerebrovascular Diseases)  32 ( 7 ) 107152 2023

Last author, Corresponding author, Accepted,  ISSN  10523057

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Objectives: Spinal dural arteriovenous fistula (sDAVF) is a rare and often underdiagnosed spinal disease. Early diagnosis is required because the deficits are reversible and delays in treatment cause permanent morbidity. Although the abnormal vascular flow void is a critical radiographic feature of sDAVF, they are not always present. A characteristic enhancement pattern of sDAVF has been recently reported as the “missing-piece” sign which can lead to the early and correct diagnosis. Methods: We presented imaging findings, treatment decisions, and the outcome of a rare case of sDAVF, in which the “missing-piece” sign appeared atypical. Results: A 60-year-old woman developed numbness and weakness in her extremities. Spinal MRI revealed longitudinal hyperintensity in the T2-weighted image, extending from the thoracic level to medulla oblongata. At first, myelopathy with inflammation or tumor was suspected because of the lack of flow voids and vascular abnormalities in CT-angiography and MR-DSA. However, we administered intravenous methylprednisolone and her symptom got worse with the appearance of the “missing-piece” sign. Then, we successfully diagnosed sDAVF by angiography. The “missing-piece” sign was considered to derive from inconsistency of the intrinsic venous system of spinal cord, with the abrupt segments without enhancement. The same etiology was considered in our case. Conclusions: Detecting the “missing-piece” sign can lead to the correct diagnosis of sDAVF, even if the sign appeared atypical.

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Depressive symptoms and carotid arteriosclerosis in very old people aged 85 years and older: A cross-sectional study by the Kawasaki Aging and Wellbeing Project.

Ryo Shikimoto, Takashi Sasaki, Yukiko Abe, Yoshinori Nishimoto, Takumi Hirata, Masaru Mimura, Yasumichi Arai

Psychiatry and Clinical Neurosciences  2023

Accepted

Association between multimorbidity, self-rated health and life satisfaction among independent, community-dwelling very old persons in Japan: longitudinal cohort analysis from the Kawasaki Ageing and Well-being Project

Ando T., Nishimoto Y., Hirata T., Abe Y., Takayama M., Maeno T., Fujishima S., Takebayashi T., Arai Y.

BMJ Open (BMJ Open)  12 ( 2 )  2022

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Objective This study aimed to identify associations between multimorbidity and subjective health outcomes among the very old persons, after adjusting for coexisting conditions such as frailty and depression. Study setting and participants This was an observational cross-sectional study involving 1012 independent, community-dwelling very old persons (507 men, 505 women; aged 85-89 years) in Kawasaki city, Japan. Outcome measures The primary outcome was the cross-sectional associations between multimorbidity and poor self-rated health (SRH) and life satisfaction using binary logistic regression. The secondary outcome was the association of subjective health with each chronic condition. Results The prevalence of multimorbidity (≥2 conditions) was 94.7%, and the average number of chronic conditions was 4.47±1.9. Multimorbidity was significantly associated with poor SRH in the adjusted model only when six or more chronic conditions were present (OR 4.80; 95% CI 1.34 to 17.11; p=0.016). Cerebrovascular disease, heart disease, respiratory disease, connective tissue disease and arthritis showed significant associations with poor SRH after multivariate adjustment. Sex-specific analysis replicated associations between multimorbidity with six or more conditions and SRH in both men and women, while the diseases with the greatest impact on SRH differed between men and women. Most conditions were not associated with low satisfaction with life scale, with the exception of arthritis (OR 1.92, 95% CI 1.32 to 2.78, p=0.001). Conclusions Multimorbidity is prevalent in the independent, community-dwelling very old persons and is associated with poor SRH when six or more conditions are present; conditions causing mobility limitations, such as cerebrovascular disease, connective tissue disease and arthritis, have a negative impact on SRH. Trial registration number UMIN000026053.

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ALDH2 p.E504K Variation and Sex Are Major Factors Associated with Current and Quitting Alcohol Drinking in Japanese Oldest Old

Takashi Sasaki, Yoshinori Nishimoto, Takumi Hirata, Yukiko Abe, Toru Takebayashi, Yasumichi Arai

Genes (Genes)  12 ( 6 )  2021

Accepted

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This study identified the factors associated with current and quitting alcohol drinking in the Oldest Old to better understand the associated factors and mechanisms underlying drinking behaviors in this age group. Results of a questionnaire for drinking behavior in 1015 Japanese Oldest Old citizens aged 85 to 89 years revealed that 56.0% of men and 24.0% of women were current drinkers. A genome-wide association study revealed that the rs671 G > A variation, which corresponds to the aldehyde dehydrogenase 2 (ALDH2) p.E504K missense variant, was significantly associated with current drinking (odds ratio: 3.8, p = 3.33 × 10−31 ). Variable selection with 41 factors and multivariate regression logistic analysis for current drinking indicated that the rs671 genotype and sex were the most significant factors in the Oldest Old. Further analysis revealed that the rs671 genotype, alcohol-associated biomarkers, a history of heart or kidney disease, and frailty score are factors associated with quitting drinking in the Oldest Old men, whereas smoking history, walking time, and depression score were factors associated with quitting drinking in the Oldest Old women. These results indicate that the ALDH2 p.E504K variation is a major factor associated with current and quitting drinking in the Japanese Oldest Old.

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LncRNA NEAT1 and amyotrophic lateral sclerosis

Yoshinori Nishimoto, Shinichi Nakagawa, Hideyuki Okano

Neurochemistry International (Neurochemistry International)  150   105175 2021

Research paper (scientific journal), Accepted,  ISSN  01970186

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Amyotrophic lateral sclerosis (ALS) is a representative neurological disease that is known to devastate entire motor neurons within a period of just a few years. Discoveries of the specific pathologies of relevant RNA-binding proteins, including TAR DNA-binding protein-43 (TDP-43) and fused in sarcoma/translocated in liposarcoma (FUS/TLS), and the causative genes of both familial and sporadic ALS have provided crucial information that could lead to a cure. In recent ALS research the GGGGCC-repeat expansion in the C9orf72 gene was identified as one of the most important pathological findings, suggesting the significance of both nuclear dysfunction due to dipeptide repeat proteins (DPRs) and RNA toxicity (such as pathological alterations of non-coding RNAs). In research on model animals carrying ALS-related molecules, the determination of whether a factor is protective or toxic has been controversial. Herein, we review the findings regarding NEAT1 RNA and C9orf72 GGGGCC repeats associated with ALS, from the viewpoint of conversion from the protective stage in the nucleus in early-phase ALS to late-phase induction of cell death. This review will provide insights for the development of RNA effectors as novel ALS treatments.

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HTRA1-Related Cerebral Small Vessel Disease: a Review of the Literature

Masahiro Uemura, Hiroaki Nozaki, Taisuke Kato, Akihide Koyama, Naoko Sakai, Shouichirou 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 (Frontiers in Neurology)  11 2020

Research paper (scientific journal), Accepted

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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.

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Sex-specific effects of apolipo proteinε 4 alleleon mortality in very old and centenarian Japanese Men

Sasaki T., Nishimoto Y., Abe Y., Takayama M., Hirose N., Okano H., Arai Y.

Journals of Gerontology - Series A Biological Sciences and Medical Sciences (Journals of Gerontology - Series A Biological Sciences and Medical Sciences)  75 ( 10 ) 1874 - 1879 2020

Accepted,  ISSN  10795006

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The apolipoprotein E4 (APOE ε4) allele has attracted attention as an age-related genetic factor, both in neurology and gerontology. To understand the effects of the APOE ε4 allele on mortality in elderly individuals, we combined Japanese prospective cohort studies comprising 535 very old individuals (85–99 years of age) and 930 centenarians (over 100 years of age) and analyzed the association between mortality rates and candidate factors, including the APOE ε4 allele. APOE genotyping revealed an inverse correlation between the APOE ε4 allele carrier rate and age. Additionally, APOE ε4 allele carrier rate in centenarian men was significantly lower than that in centenarian women. The association analysis between APOE ε4 allele carriers and all-cause mortality indicated that APOE ε4 carriers showed significantly higher mortality rates than the APOE ε4 noncarriers among men in the very old group. Further analysis using Cox proportional hazard models indicated that cause-specific mortalities, including pneumonia and severe dementia, were associated with APOE ε4 carriers. These findings indicate that the APOE ε4 allele shows phenotypic male-specific adverse effects in the very old, which would explain the high mortality rate observed in this group, resulting in a low APOE ε4 allele carrier rate in centenarian men.

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Two medullary hemorrhage cases complicated by respiratory distress in the early phase

Ryuichiro Yagi, Yoshinori Nishimoto, Satoshi Yamada, Hanae Nakashima, Kensuke Okada, Fumie Konoeda, Haruhiko Hoshino

Journal of Stroke and Cerebrovascular Diseases (Journal of Stroke and Cerebrovascular Diseases)  1 ( 1 ) 229 - 231 2019

Research paper (scientific journal), Accepted,  ISSN  10523057

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© 2018 Medullary hemorrhage is quite rare among brain stem hemorrhage cases, thus the clinical course remains unclear. In the medulla oblongata, respiratory centers are located and previous reports indicate that medullary lesions have possible relationship with acute respiratory distress syndrome. This kind of respiratory failure is commonly caused by neurogenic pulmonary edema (NPE), which is defined as noncardiac noninfectious acute respiratory distress syndrome with changes in intracranial condition including cerebrovascular events. However, to date, very few reports have described cases with medullary hemorrhage accompanied by NPE. We experienced 2 patients with medullary hemorrhages. A 65-year-old man presented with sudden onset of headache, whose head computed tomography showed right medullary hemorrhage. Another 76-year-old woman was transferred because of sudden limb weakness and diagnosed with left medullary hemorrhage. Digital subtraction angiography showed the presence of arteriovenous fistula in the medulla oblongata and drainer veins in the second case. Both cases were complicated by acute pulmonary edema in the early phase, suggesting the possible association of the medullary hemorrhage with NPE.

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Antigenic change in human influenza A(H2N2) viruses detected by using human plasma from aged and younger adult individuals

Yukimasa Matsuzawa, Kiyoko Iwatsuki-Horimoto, Yoshinori Nishimoto, Yukiko　Abe, Satoshi Fukuyama, Taiki Hamabata, Moe Okuda, Yui Go, Tokiko Watanabe, Masaki Imai, Yasumichi Arai, Ron Fouchier, Seiya Yamayoshi, Yoshihiro Kawaoka

Viruses (Viruses)  11 ( 11 ) 978 2019

Accepted

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© 2019 by the authors. Human influenza A(H2N2) viruses emerged in 1957 and were replaced by A(H3N2) viruses in 1968. The antigenicity of human H2N2 viruses has been tested by using ferret antisera or mouse and human monoclonal antibodies. Here, we examined the antigenicity of human H2N2 viruses by using human plasma samples obtained from 50 aged individuals who were born between 1928 and 1933 and from 33 younger adult individuals who were born after 1962. The aged individuals possessed higher neutralization titers against H2N2 viruses isolated in 1957 and 1963 than those against H2N2 viruses isolated in 1968, whereas the younger adults who were born between 1962 and 1968 possessed higher neutralization titers against H2N2 viruses isolated in 1963 than those against other H2N2 viruses. Antigenic cartography revealed the antigenic changes that occurred in human H2N2 viruses during circulation in humans for 11 years, as detected by ferret antisera. These results show that even though aged individuals were likely exposed to more recent H2N2 viruses that are antigenically distinct from the earlier H2N2 viruses, they did not possess high neutralizing antibody titers to the more recent viruses, suggesting immunological imprinting of these individuals with the first H2N2 viruses they encountered and that this immunological imprinting lasts for over 50 years.

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Genetic Protective Factors for Dementia Isolated by Centenarian Researches

佐々木貴史, 西本祥仁, 広瀬信義, 新井康通

BRAIN and NERVE (Brain and nerve = Shinkei kenkyu no shinpo)  71 ( 10 ) 1061 - 1070 2019

Research paper (scientific journal),  ISSN  18816096

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Due to the recent rapid increase in the number of elderly people in the world, health management and maintenance in elderly people have become important issues. Centenaria, who are older than 100 years, tend to stay independent in their daily life with maintenance of cognitive function until the later stage of their life compared with elderly people who die earlier. In this review, we summarize the characteristics of centenarians, the genetic risk and protective factors for longevity, and intersections between research on centenarians and dementia research.

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百寿者研究からの見解―健康長寿者の食生活―

Nishimoto Yoshinori

栄養-Trends of Nutrition- 3 ( 4 ) 255 - 262 2018

Research paper (scientific journal)

Aging-related frailty and sarcopenia. Frailty and sarcopenia in the centenarians.

Nishimoto Yoshinori

Clinical Calcium 28 ( 9 ) 1235 - 1240 2018

Research paper (scientific journal)

ニボルマブ投与後に筋炎合併重症筋無力症を発症した1例

此枝史恵, 鈴木重明, 西本祥仁, 星野晴彦, 高木誠

臨床神経学 57 ( 7 ) 373 - 377 2017

Research paper (scientific journal), Accepted

Establishment of in vitro FUS-associated Familial Amyotrophic Lateral Sclerosis Model using Human induced Pluripotent Stem Cells.

Naoki Ichiyanagi, Koki Fujimori, Masato Yano, Chikako Ishihara-Fujisaki, Takefumi Sone, Tetsuya Akiyama, Yohei Okada, Wado Akamatsu, Takuya Matsumoto, Mitsuru Ishikawa, Yoshinori Nishimoto, Yasuharu Ishihara, Tetsushi Sakuma, Takashi Yamamoto, Hitomi Tsuiji, Naoki Suzuki, Hitoshi Warita, Masashi Aoki, Hideyuki Okano

Stem Cell Reports 12 ( 6 ) 496 - 510 2016

Research paper (scientific journal), Accepted

Characteristic features and progression of abnormalities on MRI for CARASIL.

Nozaki H, Sekine Y, Fukutake T, Nishimoto Y, Shimoe Y, Shirata A, Yanagawa S, Hirayama M, Tamura M, Nishizawa M, Onodera O.

Neurology 85 ( 5 ) 459 - 463 2015

Research paper (scientific journal), Accepted

Cadherin-7 regulates mossy fiber connectivity in the cerebellum.

Kuwako K, Nishimoto Y, Kawase S, Okano HJ, Okano H.

Cell Reports 9 ( 1 ) 311 - 323 2014

Research paper (scientific journal), Accepted

A Japanese case of hereditary hemorrhagic telangiectasia type 2 (HHT2) with a novel mutation, c.154A>C (p.Thr52Pro), in the ALK1/ACVRL1 gene.

Nishimoto Y, Morisaki H, Yamada O, Ichinose Y, Suzuki N.

Neurology and Clinical Neuroscience 4 ( 2 ) 126 - 128 2014

Research paper (scientific journal), Accepted

CARASILのMRI所見

野崎洋明, 関根有美, 西澤正豊, 小野寺理, 福武敏夫, 下江豊, 平山幹夫, 柳川宗平, 西本祥仁

新潟医学会雑誌 127 ( 6 ) 333 - 334 2013

Research paper (scientific journal)

Cellular toxicity induced by the 26-kDa fragment and amyotrophic lateral sclerosis (ALS)-associated mutant forms of TDP-43 in human embryonic stem cell-derived motor neurons.

Nishimoto Y, Okano HJ, Imai T, Poole AJ, Suzuki N, Keirstead HS, Okano H.

Neurology and Clinical Neuroscience 1 ( 1 ) 24 - 31 2013

Research paper (scientific journal), Accepted

The long non-coding RNA nuclear-enriched abundant transcript 1_2 induces paraspeckle formation in the motor neuron during the early phase of amyotrophic lateral sclerosis.

Nishimoto Y, Nakagawa S, Hirose T, Okano HJ, Takao M, Shibata S, Suyama S, Kuwako K, Imai T, Murayama S, Suzuki N, Okano H.

Molecular Brain 6 ( 31 )  2013

Research paper (scientific journal), Accepted

RNA-binding protein Musashi1 modulates glioma cell growth through the post-transcriptional regulation of Notch and PI3 kinase/Akt signaling pathways.

Muto J, Imai T, Ogawa D, Nishimoto Y, Okada Y, Mabuchi Y, Kawase T, Iwanami A, Mischel PS, Saya H, Yoshida K, Matsuzaki Y, Okano H.

PLoS One 7 ( 3 ) e33431 2012

Research paper (scientific journal), Accepted

RNA editing of the Q/R site of GluA2 in different cultured cell lines that constitutively express different levels of RNA editing enzyme ADAR2.

Yamashita T, Tadami C, Nishimoto Y, Hideyama T, Kimura D, Suzuki T, Kwak S.

Neuroscience Research 73 ( 1 ) 42 - 48 2012

Research paper (scientific journal), Accepted

Neuroaxonal integrity evaluated by MR spectroscopy in a case of CARASIL.

Nishimoto Y, Shibata M, Onodera O, Suzuki N.

Journal of Neurology, Neurosurgery and Psychiatry 82 ( 8 ) 860 - 861 2011

Research paper (scientific journal), Accepted

A novel mutation in the HTRA1 gene causes CARASIL without alopecia.

Nishimoto Y, Shibata M, Nihonmatsu M, Nozaki H, Shiga A, Shirata A, Yamane K, Kosakai A, Takahashi K, Nishizawa M, Onodera O, Suzuki N.

Neurology 76 ( 15 ) 1353 - 1355 2011

Research paper (scientific journal), Accepted

Identification of a novel intronic enhancer responsible for the transcriptional regulation of musashi1 in neural stem/progenitor cells.

Kawase S, Imai T, Miyauchi-Hara C, Yaguchi K, Nishimoto Y, Fukami S, Matsuzaki Y, Miyawaki A, Itohara S, Okano H.

Molecular Brain 4 ( 14 )  2011

Research paper (scientific journal), Accepted

Slow-progressive ataxia with a methionine-to-arginine point mutation in codon 232 in the prion protein gene (PRNP).

Nishimoto Y, Ito D, Suzuki S, Shimizu T, Kitamoto T, Suzuki N.

Clinical Neurology and Neurosurgery 113 ( 8 ) 696 - 698 2011

Research paper (scientific journal), Accepted

Headache associated with myasthenia gravis: the impact of mild ocular symptoms.

Nishimoto Y, Suzuki S, Utsugisawa K, Nagane Y, Shibata M, Shimizu T, Suzuki N.

Autoimmune Diseases 2011   840364 2011

Research paper (scientific journal), Accepted

microRNA-206によるALSモデルマウスの疾患進行抑制と神経筋接合部におけるシナプス再生の促進

西本祥仁

MEDICAL BRIEFS IN Brain & Nerve 18 ( 2 ) 8 - 9 2011

Research paper (scientific journal)

Ataxin-2グルタミン鎖伸長と神経変性疾患－ALS, PSP発症リスクとの相関性について

Nishimoto Yoshinori

Cognition and Dementia 10 ( 4 ) 58 - 59 2011

Research paper (scientific journal)

一過性全健忘でのヒト海馬CA1領域の限局性病変は空間ナビゲーション学習を障害する

西本祥仁, 伊東大介

MEDICAL BRIEFS IN Brain & Nerve 18 ( 3 ) 6 - 7 2011

Research paper (scientific journal)

TDP-43タンパク新規アイソフォームの同定と35-kDa封入体特性の検討

Nishimoto Yoshinori

最新医学 65 ( 7 ) 1579 - 1587 2010

Research paper (scientific journal)

Characterization of alternative isoforms and inclusion body of the TAR DNA-binding protein-43.

Nishimoto Y, Ito D, Yagi T, Nihei Y, Tsunoda Y, Suzuki N.

Journal of Biological Chemistry 285 ( 1 ) 608 - 619 2010

Research paper (scientific journal), Accepted

Novel etiological and therapeutic strategies for neurodiseases: RNA editing enzyme abnormality in sporadic amyotrophic lateral sclerosis.

Hideyama T, Yamashita T, Nishimoto Y, Suzuki T, Kwak S.

Journal of Pharmacological Science 113 ( 1 ) 9 - 13 2010

Research paper (scientific journal), Accepted

New insight into cancer therapeutics: induction of differentiation by regulating the Musashi/Numb/Notch pathway.

Nishimoto Y, Okano H.

Cell Research 20 ( 10 ) 1083 - 1085 2010

Research paper (scientific journal), Accepted

血中シグナル蛋白に基づいたアルツハイマー病臨床診断の分類と予測

西本祥仁, 伊東大介

MEDICAL BRIEFS IN Brain & Nerve 17 ( 1 ) 6 - 7 2009

Research paper (scientific journal)

Newly identified ADAR-mediated A-to-I editing positions as a tool for ALS research.

Kwak S, Nishimoto Y, Yamashita T

RNA Biology 5 ( 4 ) 193 - 197 2008

Research paper (scientific journal)

Determination of editors at the novel A-to-I editing positions.

Nishimoto Y, Yamashita T, Hideyama T, Tsuji S, Suzuki N, Kwak S

Neuroscience Research 61 ( 2 ) 201 - 206 2008

Doctoral thesis, Accepted

Case of consciousness disturbance following a fever with spreading lesion over the bilateral splenia of the corpus callosum on MRI

Nishimoto Y, Isozumi K, Ushioda R, Komatsumoto S, Fukuuchi Y

Rinsho Shinkeigaku 47 ( 2-3 ) 73 - 78 2007

Research paper (scientific journal), Accepted

AMPA受容体サブユニットGluR2のRNA編集とALSにおける神経細胞死

西本祥仁, 日出山拓人, 河原行郎, 郭 伸

Clinical Neuroscience 24 ( 2 ) 222 - 225 2006

Research paper (scientific journal)

ALSとRNA編集

西本祥仁, 日出山拓人, 河原行郎, 郭 伸

医学のあゆみ 215 ( 8 ) 683 - 687 2005

Research paper (scientific journal)

グルタミン酸受容体, イオノトロピック, AMPA2(GRIA2)

西本祥仁, 日出山拓人, 郭 伸

生体の科学 56 ( 5 ) 424 - 425 2005

Research paper (scientific journal)

脳卒中における興奮性アミノ酸毒性

西本祥仁, 日出山拓人, 郭 伸

Current Therapy 23 ( 10 ) 94 - 95 2005

Research paper (scientific journal)