Publications by authors named "Takeo Kato"

277 Publications

Epidemiology of coronavirus disease 2019 in Yamagata Prefecture, Japan, January-May 2020: The importance of retrospective contact tracing.

Jpn J Infect Dis 2021 Mar 31. Epub 2021 Mar 31.

Yamagata Prefectural Institute of Public Health, Japan.

Public health interventions have served an important role in controlling coronavirus disease 2019 (COVID-19), a rapidly spreading infectious disease. To contribute to future COVID-19 countermeasures, we aimed at verifying the results of countermeasures achieved by public health centers (PHCs) against the first wave of COVID-19 in Yamagata Prefecture, Japan. During January-May 2020, 1,253 patients suspected of SARS-CoV-2 infection were invited for testing. Simultaneously, based on retrospective contact tracings, PHCs investigated the infection sources and transmission routes of laboratory-confirmed COVID-19 cases and tested 928 contacts. Consequently, 69 cases were confirmed during March 31 - May 4, 58 (84.1%; 95% confidence interval 75.5-92.7) of whom were found from contacts. The spread of infection was triggered by cases harboring epidemiological links outside of Yamagata. Then, the number of cases increased rapidly. However, PHCs identified epidemiological links in 61 (88.4%; 95% confidence interval 80.8-96.0) of the 69 cases and transmission chains up to the fifth generation. Finally, the spread of infection ended after approximately one month. Our results indicate that the identification of infection sources and active case finding from contacts based on retrospective contact tracing was likely to be an effective strategy to end the first wave of COVID-19 in Yamagata.
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http://dx.doi.org/10.7883/yoken.JJID.2020.1073DOI Listing
March 2021

Guidelines for Management of Idiopathic Normal Pressure Hydrocephalus (Third Edition): Endorsed by the Japanese Society of Normal Pressure Hydrocephalus.

Neurol Med Chir (Tokyo) 2021 Feb 15;61(2):63-97. Epub 2021 Jan 15.

Department of Behavioral Neurology and Neuropsychiatry, Osaka University United Graduate School of Child Development, Suita, Osaka, Japan.

Among the various disorders that manifest with gait disturbance, cognitive impairment, and urinary incontinence in the elderly population, idiopathic normal pressure hydrocephalus (iNPH) is becoming of great importance. The first edition of these guidelines for management of iNPH was published in 2004, and the second edition in 2012, to provide a series of timely, evidence-based recommendations related to iNPH. Since the last edition, clinical awareness of iNPH has risen dramatically, and clinical and basic research efforts on iNPH have increased significantly. This third edition of the guidelines was made to share these ideas with the international community and to promote international research on iNPH. The revision of the guidelines was undertaken by a multidisciplinary expert working group of the Japanese Society of Normal Pressure Hydrocephalus in conjunction with the Japanese Ministry of Health, Labour and Welfare research project. This revision proposes a new classification for NPH. The category of iNPH is clearly distinguished from NPH with congenital/developmental and acquired etiologies. Additionally, the essential role of disproportionately enlarged subarachnoid-space hydrocephalus (DESH) in the imaging diagnosis and decision for further management of iNPH is discussed in this edition. We created an algorithm for diagnosis and decision for shunt management. Diagnosis by biomarkers that distinguish prognosis has been also initiated. Therefore, diagnosis and treatment of iNPH have entered a new phase. We hope that this third edition of the guidelines will help patients, their families, and healthcare professionals involved in treating iNPH.
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http://dx.doi.org/10.2176/nmc.st.2020-0292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905302PMC
February 2021

Ketogenic Diet Therapy for Intractable Epilepsy in Infantile Alexander Disease: A Small Case Series and Analyses of Astroglial Chemokines and Proinflammatory Cytokines.

Epilepsy Res 2021 Feb 3;170:106519. Epub 2020 Dec 3.

Department of Pediatrics, Nara Medical University, Nara, Japan.

In infantile Alexander disease (iAxD), one of the serious symptoms is intractable epilepsy, and some reports have suggested that neuroinflammation may be involved in the pathophysiology of the disease. Drug-resistant seizures adversely affect not only the quality of life of the caregivers and patients, but also patients' lifespan. Thus, controlling epilepsy is clinically important. For intractable childhood epilepsy, ketogenic diet therapy (KDT) is well-established, but its effects on iAxD have not been characterized. Here, we describe the use of KDT in three iAxD patients experiencing drug-resistant seizures. In all three cases, the formerly intractable epilepsies were well controlled by KDT. However, the brain magnetic resonance imaging findings deteriorated even after the epilepsy was controlled. In addition, the concentrations of monocyte chemotactic protein-1 and proinflammatory cytokines in the cerebrospinal fluid of the patients remained still high. KDT is effective in controlling epilepsy in iAxD. Our results clinically support previous reports arguing the involvement of neuroinflammation in the pathophysiology of iAxD. Although KDT cannot prevent disease progression, earlier initiation might contribute to a better prognosis.
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http://dx.doi.org/10.1016/j.eplepsyres.2020.106519DOI Listing
February 2021

Gaussian Curvature Entropy for Curved Surface Shape Generation.

Entropy (Basel) 2020 Mar 18;22(3). Epub 2020 Mar 18.

Department of Mechanical Engineering, Keio University, Yokohama 223-8522, Japan.

The overall shape features that emerge from combinations of shape elements, such as "complexity" and "order", are important in designing shapes of industrial products. However, controlling the features of shapes is difficult and depends on the experience and intuition of designers. Among these features, "complexity" is said to have an influence on the "beauty" and "preference" of shapes. This research proposed a Gaussian curvature entropy as a "complexity" index of a curved surface shape. The proposed index is calculated based on Gaussian curvature, which is obtained by the sampling and quantization of a curved surface shape and validated by the sensory evaluation experiment while using two types of sample shapes. The result indicates the correspondence of the index to perceived "complexity" (the determination coefficient is greater than 0.8). Additionally, this research constructed a shape generation method that was based on the index as a car design supporting apparatus, in which the designers can refer many shapes generated by controlling "complexity". The applicability of the proposed method was confirmed by the experiment while using the generated shapes.
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http://dx.doi.org/10.3390/e22030353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7516826PMC
March 2020

A multi-center, prospective study on the progression rate of asymptomatic ventriculomegaly with features of idiopathic normal pressure hydrocephalus on magnetic resonance imaging to idiopathic normal pressure hydrocephalus.

J Neurol Sci 2020 Dec 3;419:117166. Epub 2020 Oct 3.

Division of Neurology and Clinical Neuroscience, Department of Internal Medicine III, Yamagata University School of Medicine, Yamagata, Japan. Electronic address:

Introduction: Our previous community-based study demonstrated that some individuals with AVIM [asymptomatic ventriculomegaly with features of idiopathic normal pressure hydrocephalus (iNPH) on magnetic resonance imaging (MRI)] progressed to iNPH in several years. In this hospital-based study, we investigated the progression rate from AVIM to iNPH and its possible predictors.

Methods: We conducted a prospective study of participants with AVIM from several medical institutions/hospitals in Japan. AVIM is defined as "asymptomatic ventriculomegaly with features of iNPH on MRI"; in the present study, asymptomatic was defined as "0 (no symptoms) or 1 (presence of only subjective, but not objective, symptoms) on the iNPH Grading Scale (iNPH-GS)." We also measured possible predicting factors for AVIM-to-iNPH progression, including age, sex, body weight, blood pressure, diabetes mellitus, dyslipidemia, history of mental disease/head injury/sinusitis/smoking/alcohol-intake, Evans index, and the presence of DESH (disproportionately enlarged subarachnoid-space hydrocephalus) findings on brain MRI, and analyzed these potential predictive values.

Results: In 2012, 93 participants with AVIM were registered and enrolled in the study. Of these, 52 participants were able to be tracked for three years (until 2015). Of the 52 participants, 27 (52%) developed iNPH during the follow-up period (11 definite, 6 probable, and 10 possible iNPH), whereas 25 participants remained asymptomatic in 2015. Among the possible predictive factors examined, the baseline scores of iNPH-GS predicted the AVIM-to-iNPH progression.

Conclusions: The multicenter prospective study demonstrated that the progression rate from AVIM to iNPH was ~17% per year, and the baseline scores of iNPH-GS predicted the AVIM-to-iNPH progression.
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http://dx.doi.org/10.1016/j.jns.2020.117166DOI Listing
December 2020

Integrated DNA methylation analysis reveals a potential role for ANKRD30B in Williams syndrome.

Neuropsychopharmacology 2020 09 18;45(10):1627-1636. Epub 2020 Apr 18.

Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Williams syndrome (WS) is a rare genetic disorder, caused by a microdeletion at the 7q11.23 region. WS exhibits a wide spectrum of features including hypersociability, which contrasts with social deficits typically associated with autism spectrum disorders. The phenotypic variability in WS likely involves epigenetic modifications; however, the nature of these events remains unclear. To better understand the role of epigenetics in WS phenotypes, we integrated DNA methylation and gene expression profiles in blood from patients with WS and controls. From these studies, 380 differentially methylated positions (DMPs), located throughout the genome, were identified. Systems-level analysis revealed multiple co-methylation modules linked to intermediate phenotypes of WS, with the top-scoring module related to neurogenesis and development of the central nervous system. Notably, ANKRD30B, a promising hub gene, was significantly hypermethylated in blood and downregulated in brain tissue from individuals with WS. Most CpG sites of ANKRD30B in blood were significantly correlated with brain regions. Furthermore, analyses of gene regulatory networks (GRNs) yielded master regulator transcription factors associated with WS. Taken together, this systems-level approach highlights the role of epigenetics in WS, and provides a possible explanation for the complex phenotypes observed in patients with WS.
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http://dx.doi.org/10.1038/s41386-020-0675-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419304PMC
September 2020

Reply to: MIDN locus structural variants and Parkinson's disease risk.

Ann Clin Transl Neurol 2020 04 22;7(4):604-605. Epub 2020 Mar 22.

Department of Pharmacology, Yamagata University School of Medicine, Yamagata, Japan.

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http://dx.doi.org/10.1002/acn3.51011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187700PMC
April 2020

Dysregulation of the oxytocin receptor gene in Williams syndrome.

Psychoneuroendocrinology 2020 05 20;115:104631. Epub 2020 Feb 20.

Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan. Electronic address:

Williams syndrome (WS) is caused by a microdeletion of chromosome 7q11.23, and is characterized by various physical and cognitive symptoms. In particular, WS is characterized by hypersocial (overfriendly) behavior; WS has gained attention as aspects of the WS phenotype contrast with those of autism spectrum disorder (ASD). The oxytocin receptor gene (OXTR) contributes to social phenotypes in relation to regulation of oxytocin (OXT) secretion. Additionally, mounting evidence has recently shown that DNA methylation of OXTR is associated with human social behavior. However, the role of OXTR in WS remains unclear. This study investigated the regulation of OXTR in WS. We examined the gene expression levels in blood from WS patients and controls, and then analyzed the methylation levels in two independent cohorts. We showed that OXTR was down-regulated and hypermethylated in WS patients compared to controls. Our findings may provide an insight into OXTR in mediating complex social phenotypes in WS.
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http://dx.doi.org/10.1016/j.psyneuen.2020.104631DOI Listing
May 2020

A metastatic malignancy of unknown primary origin in a 12-year-old girl with anti-N-methyl-d-aspartate encephalitis.

Pediatr Int 2020 Feb 13;62(2):238-240. Epub 2020 Feb 13.

Department of Pediatrics, Hyogo Prefectural Amagasaki General Medical Center, Amagasaki, Japan.

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http://dx.doi.org/10.1111/ped.14084DOI Listing
February 2020

Midnolin is a confirmed genetic risk factor for Parkinson's disease.

Ann Clin Transl Neurol 2019 11 6;6(11):2205-2211. Epub 2019 Oct 6.

Department of Pharmacology, Yamagata University School of Medicine, Yamagata, Japan.

Objective: Genetic analysis of patients with familial Parkinson's disease (PD) identified many causative genes. However, the majority of PD cases are sporadic, and the mechanisms of onset still remain unclear. Previously, we found that Midnolin (MIDN) is associated with PD in a Yamagata (Japan) cohort study and that MIDN regulates neurite outgrowth and Parkin expression in neuronal cells. In the present study, we aimed to replicate the genetic association between MIDN and PD in a large British population cohort.

Methods: In this replication study, we analyzed the copy number variations and single-nucleotide polymorphisms of the MIDN gene in a large British population on a case-control genome-wide association study dataset including 2,860 controls and 2,168 PD patients.

Results: There was significant copy number loss in the MIDN gene with an odds ratio of 4.35 (P < 2.2 × 10 ). Furthermore, there were many patients in both the British and Yamagata case groups who have a long spanning deletion. The odds ratio dramatically increased to 22.3 (P = 3.59 × 10 ) when a deletion spanning more than 50,000 bp was defined as the copy number loss. There were no significant differences between the controls and study cases for two relatively frequent single-nucleotide polymorphisms (rs3746106 and rs3746107).

Interpretation: We showed the strong genetic association of MIDN with PD development in a British population and in a Japanese population, suggesting MIDN is a confirmed and universal genetic risk factor for PD.
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http://dx.doi.org/10.1002/acn3.50914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856597PMC
November 2019

Genetic abnormalities in a large cohort of Coffin-Siris syndrome patients.

J Hum Genet 2019 Dec 17;64(12):1173-1186. Epub 2019 Sep 17.

Asahikawa-Kosei General Hospital, Hokkaido, Japan.

Coffin-Siris syndrome (CSS, MIM#135900) is a congenital disorder characterized by coarse facial features, intellectual disability, and hypoplasia of the fifth digit and nails. Pathogenic variants for CSS have been found in genes encoding proteins in the BAF (BRG1-associated factor) chromatin-remodeling complex. To date, more than 150 CSS patients with pathogenic variants in nine BAF-related genes have been reported. We previously reported 71 patients of whom 39 had pathogenic variants. Since then, we have recruited an additional 182 CSS-suspected patients. We performed comprehensive genetic analysis on these 182 patients and on the previously unresolved 32 patients, targeting pathogenic single nucleotide variants, short insertions/deletions and copy number variations (CNVs). We confirmed 78 pathogenic variations in 78 patients. Pathogenic variations in ARID1B, SMARCB1, SMARCA4, ARID1A, SOX11, SMARCE1, and PHF6 were identified in 48, 8, 7, 6, 4, 1, and 1 patients, respectively. In addition, we found three CNVs including SMARCA2. Of particular note, we found a partial deletion of SMARCB1 in one CSS patient and we thoroughly investigated the resulting abnormal transcripts.
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http://dx.doi.org/10.1038/s10038-019-0667-4DOI Listing
December 2019

Inflammatory neuropathology of infantile Alexander disease: A case report.

Brain Dev 2020 Jan 24;42(1):64-68. Epub 2019 Aug 24.

Department of Neurology, Graduate School of Medicine, Kyoto Prefectural University of Medicine, Japan.

Background: Alexander disease (AxD) is a rare fatal leukodystrophy caused by a dominant missense mutation in the glial fibrillary acidic protein. In a mouse model of AxD, the pathological astrocyte causes a pronounced immune response. The inflammatory environment in the brain might play an important role in the neuronal dysfunction of AxD.

Case: A 3-month-old girl diagnosed with infantile AxD presented with severe intractable seizures and a deteriorated neurological state. Steroid pulse therapy was effective at preventing the epileptic activity and progressive white matter abnormalities on magnetic resonance images, but the effect was temporary. Levels of interleukin (IL)-6, IL-8, and macrophage chemotactic protein 1 (MCP-1) in the cerebrospinal fluid were high at onset and reduced transiently after steroid pulse therapy.

Discussion: These results suggest that inflammatory responses of astrocyte and microglia can contribute to the neuropathology of AxD. Robust immunomodulation that targets activated astrocytes and microglia may be a novel therapeutic strategy to improve neurological prognosis in AxD.
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http://dx.doi.org/10.1016/j.braindev.2019.07.010DOI Listing
January 2020

Surface plasmon polaritons in thin-film Weyl semimetals.

J Phys Condens Matter 2019 Jul 9;31(30):305001. Epub 2019 Apr 9.

Institute for Solid State Physics, University of Tokyo, Kashiwa, 277-8581, Japan.

We theoretically investigate surface plasmon polaritons propagating in the thin-film Weyl semimetals. We show how the properties of surface plasmon polaritons are affected by hybridization between plasmons localized at the two metal-dielectric interfaces. Generally, this hybridization results in new mixed plasmon modes, which are called short-range surface plasmons and long-range surface plasmons, respectively. We calculate dispersion curves of these mixed modes for three principle configurations of the axion vector describing axial anomaly in Weyl semimetals. We show that the partial lack of the dispersion and the non-reciprocity can be controlled by fine-tuning of the thickness of the Weyl semimetals, the dielectric constants of the outer insulators, and the direction of the axion vector.
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http://dx.doi.org/10.1088/1361-648X/ab17b3DOI Listing
July 2019

Background Risk Factors Associated with Shunt Intervention for Possible Idiopathic Normal Pressure Hydrocephalus: A Nationwide Hospital-Based Survey in Japan.

J Alzheimers Dis 2019 ;68(2):735-744

Department of Neurosurgery, Juntendo University Faculty of Medicine, Tokyo, Japan.

Background: Patients with idiopathic normal-pressure hydrocephalus (iNPH) are typically older adults with multiple comorbidities that are associated with a reduction in the efficacy of iNPH treatment via cerebrospinal fluid (CSF) shunt placement.

Objective: The present study aimed to investigate the effectiveness of CSF shunt for iNPH using data from a nationwide epidemiological survey in Japan.

Methods: We examined 1,423 patients (581 women) aged ≥60 years (median age [25%-75%]: 77 [73-80] years) who were diagnosed with iNPH following a hospital visit in 2012. Patients who experienced an improvement of at least one modified Rankin Scale (mRS) grade after the CSF shunt were classified as "improvement" while the remaining patients were classified as "non-improvement." The efficacy of the shunt intervention (n = 842) was analyzed using a binomial logistic regression analysis.

Results: An analysis of risk factors associated with shunt placement in patients with mRS grade 2 revealed an association between comorbid chronic ischemic lesions (odds ratio [OR], 2.28; 95% confidence interval [CI], 1.11-4.67; p = 0.025) and cervical spondylosis (OR, 3.62; 95% CI, 1.15-11.34; p = 0.027). Patients with mRS grade 3 at study entry had an association with comorbid Alzheimer's disease (OR, 3.02; 95% CI, 1.44-6.31; p = 0.003).

Conclusions: The results presented here showed that any age-related risk is minimal and should not be cause for rejection of surgical treatment options. Clinical decisions regarding CSF shunt should be individualized to each patient, with adequate consideration of the relative risks and benefits, including maximizing a healthy life expectancy.
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http://dx.doi.org/10.3233/JAD-180955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6484254PMC
July 2020

[An adult female with proline-rich transmembrane protein 2 related paroxysmal disorders manifesting paroxysmal kinesigenic choreoathetosis and epileptic seizures].

Rinsho Shinkeigaku 2019 Mar 28;59(3):144-148. Epub 2019 Feb 28.

Department of Neurology, Kyoto University Graduate School of Medicine.

A 21-year-old woman presented with a chief complaint of generalized tonic-clonic seizures occurring once a month at night since the age of 14. The patient was treated with clonazepam plus levetiracetam, but seizure frequency was not reduced. After the detailed re-examination of her history of illness, it was revealed that she has been suffering from transient and recurrent choreoathetoid attacks triggered by sudden voluntary movements since she was a junior high school student, and it recently increased in frequency. Neither she nor her family recognize that it was significant to describe to the doctors. She was diagnosed as a complex of paroxysmal kinesigenic choreoathetosis (PKC) and its related conditions. Direct sequencing of proline-rich transmembrane protein 2 (PRRT2) revealed the most frequently described gene mutation, (NM_145239.2:c.649dupC), among PRRT2-related paroxysmal disorders. PKC and seizures were readily controlled with small dose of carbamazepine. Given the broad spectrum of PRRT2-related paroxysmal disorders, assessment of potential clinical complication of paroxysmal disorders including PKC might therefore be critical.
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http://dx.doi.org/10.5692/clinicalneurol.cn-001228DOI Listing
March 2019

Tooth Loss-associated Cognitive Impairment in the Elderly: A Community-based Study in Japan.

Intern Med 2019 May 10;58(10):1411-1416. Epub 2019 Jan 10.

Division of Neurology and Clinical Neuroscience, Department of Internal Medicine III, Yamagata University Faculty of Medicine, Japan.

Objective Dementia is a major cause of disruption for a healthy life expectancy in Japan. It has been suggested that the number of teeth is a modifiable risk factor for cognitive impairment and dementia. We therefore examined the possible association between the cognitive function and the number of natural and artificial teeth in community-dwelling Japanese elderly individuals. Methods Among the participants in our prospective, community-based study, 210 elderly individuals (103 men and 107 women; 78.1±4.9 years; mean age±standard deviation) underwent both dental examinations and a Mini-Mental State Examination (MMSE), as well as various medical checkups, in 2016 and 2017. Results The number of natural teeth was significantly associated with an individual's MMSE score. The percentage of cognitively normal subjects (MMSE scores: 27-30) decreased significantly with a decrease in the number of natural teeth. Among the MMSE items, the calculation ability was significantly and independently associated with the number of natural teeth. Regression was calculated as the predicted score of MMSE =21+0.3× (years of schooling) +0.1× (number of natural teeth). Among individuals with 19 or fewer natural teeth, those who had a total of 20 teeth or more, including both natural and artificial teeth, had significantly higher MMSE scores than those who had 19 or fewer natural and artificial teeth combined. Conclusion The number of natural teeth was significantly associated with the cognitive function, especially the calculation ability, and the use of artificial teeth was associated with the preservation of the cognitive function in community-dwelling elderly individuals.
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http://dx.doi.org/10.2169/internalmedicine.1896-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548929PMC
May 2019

Cognitive impairment, brain ischemia and shorter telomeres are predictors of mortality in the Japanese elderly: A 13-year prospective community-based study.

J Neurol Sci 2019 02 31;397:129-134. Epub 2018 Dec 31.

Division of Neurology and Clinical Neuroscience, Department of Internal Medicine III, Yamagata University School of Medicine, Yamagata, Japan. Electronic address:

Objective: To examine whether cognitive impairment, deep white matter hyperintensity (DWMH) on brain MRI, and shorter telomere length would be predictors of mortality in community-dwelling Japanese elderly.

Methods: We followed 259 individuals (74% of all the residents at age 70) from age 70 to 83 years. The mean observation period was 133 ± 34 months. The key clinical characteristics examined included DWMH on brain MRI and cognitive function. Telomere length was also measured in 81 subjects. Both univariate and multivariate analyses were performed.

Results: Of the 259 subjects, 69 subjects (30 men, 39 women; 26.6%) died during the follow-up period. Cognitive impairment, smoking habits, diabetes mellitus, and moderate to severe DWMH were significant predictors of total mortality in univariate analysis. However, only cognitive impairment and moderate to severe DWMH remained as significant independent predictors of death in multivariate analysis. The rate of mortality increased with additional number of risk factors (cognitive impairment and DWMH). The total mortality of subjects with both cognitive impairment and DWMH was 71.4%. The median telomere length was 7.8 kb in the deceased and 8.2 kb in the living subjects. The deceased subjects had significantly shorter telomere length (P = .0025) than the living subjects. Telomere length with moderate to severe DWMH was higher than without moderate to severe DWMH on brain MRI (P = .017).

Conclusions: The present study revealed that cognitive impairment, DWMH, and shorter telomere length were significant predictors of total mortality in the community-dwelling Japanese elderly. Furthermore, the combination of cognitive impairment and DWMH increased the mortality rate, as compared with a single risk factor. It is also clarified that a significant difference was present in telomere length by severity of DWMH.
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http://dx.doi.org/10.1016/j.jns.2018.12.038DOI Listing
February 2019

Copy number loss in is common among Finnish and Norwegian patients with iNPH.

Neurol Genet 2018 Dec 3;4(6):e291. Epub 2018 Dec 3.

Department of Neurosurgery (V.E.K., A. Jokinen, I.J., J.-M.L., A. Junkkari, J.E.J., V.L.), Kuopio University Hospital and University of Eastern Finland; Institute of Clinical Medicine-Neurology (S.H., M.H., H. Soininen, A.M.K.), University of Eastern Finland, Kuopio; Department of Neurosurgery (M.O., K.L.), University of Helsinki and Helsinki University Hospital; Clinical Neurosciences (C.A., A.K., J.F., J.R.), Department of Neurosurgery, University of Turku and Turku University Hospital; Department of Neurosurgery (A.R.), Tampere University Hospital; Unit of Clinical Neuroscience (M. Kauppinen, V.L.), Neurosurgery, University of Oulu and Medical Research Center, Oulu University Hospital; Institute of Biomedicine (M.H.), University of Eastern Finland, Kuopio; Analytical and Translational Genetics Unit (M. Kurki), Department of Medicine, Massachusetts General Hospital; Program in Medical and Population Genetics (M. Kurki), Broad Institute of MIT and Harvard; Stanley Center for Psychiatric Research (M. Kurki), Broad Institute for Harvard and MIT; Department of Neurology (H. Sato, T.K.), Hematology, Metabolism, Endocrinology and Diabetology, Yamagata University Faculty of Medicine, Japan; Medical Research Center (A.M.R.), Oulu University Hospital, Finland; Unit of Clinical Neuroscience (A.M.R.), Neurology, University of Oulu, Finland; Department of Neurosurgery (P.K.E.), Oslo University Hospital-Rikshospitalet; and Institute of Clinical Medicine (P.K.E.), Faculty of Medicine, University of Oslo, Norway.

Objective: To evaluate the role of the copy number loss in in a Caucasian population.

Methods: Five hundred sixty-seven Finnish and 377 Norwegian patients with idiopathic normal pressure hydrocephalus (iNPH) were genotyped and compared with 508 Finnish elderly, neurologically healthy controls. The copy number loss in intron 2 of was determined using quantitative PCR.

Results: The copy number loss in intron 2 of was detected in 10% of Finnish (odds ratio [OR] = 1.9, = 0.0078) and in 21% of Norwegian (OR = 4.7, < 0.0001) patients with iNPH compared with 5.4% in Finnish controls. No copy number gains in were detected in patients with iNPH or healthy controls. The carrier status did not provide any prognostic value for the effect of shunt surgery in either population. Moreover, no difference was detected in the prevalence of hypertension or T2DM between copy number loss carriers and noncarriers.

Conclusions: This is the largest and the first multinational study reporting the increased prevalence of the copy number loss in intron 2 of among patients with iNPH, providing further evidence of its role in iNPH. The pathogenic role still remains unclear, requiring further study.
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http://dx.doi.org/10.1212/NXG.0000000000000291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6283454PMC
December 2018

Integrative network analysis reveals biological pathways associated with Williams syndrome.

J Child Psychol Psychiatry 2019 05 25;60(5):585-598. Epub 2018 Oct 25.

Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Background: Williams syndrome (WS) is a neurodevelopmental disorder that has been attributed to heterozygous deletions in chromosome 7q11.23 and exhibits a variety of physical, cognitive, and behavioral features. However, the genetic basis of this phenotypic variability is unclear. In this study, we identified genetic clues underlying these complex phenotypes.

Methods: Neurobehavioral function was assessed in WS patients and healthy controls. Total RNA was extracted from peripheral blood and subjected to microarray analysis, RNA-sequencing, and qRT-PCR. Weighted gene co-expression network analysis was performed to identify specific alterations related to intermediate disease phenotypes. To functionally interpret each WS-related module, gene ontology and disease-related gene enrichment were examined. We also investigated the micro (mi)RNA expression profiles and miRNA co-expression networks to better explain the regulation of the transcriptome in WS.

Results: Our analysis identified four significant co-expression modules related to intermediate WS phenotypes. Notably, the three upregulated WS-related modules were composed exclusively of genes located outside the 7q11.23 region. They were significantly enriched in genes related to B-cell activation, RNA processing, and RNA transport. BCL11A, which is known for its association with speech disorders and intellectual disabilities, was identified as one of the hub genes in the top WS-related module. Finally, these key upregulated mRNA co-expression modules appear to be inversely correlated with a specific downregulated WS-related miRNA co-expression module.

Conclusions: Dysregulation of the mRNA/miRNA network involving genes outside of the 7q11.23 region is likely related to the complex phenotypes observed in WS patients.
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http://dx.doi.org/10.1111/jcpp.12999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7379192PMC
May 2019

Transient extreme spindles in a young child with anti-NMDAR encephalitis: A case report.

Brain Dev 2019 Feb 29;41(2):210-213. Epub 2018 Sep 29.

Department of Pediatric Neurology, Hyogo Prefectural Amagasaki General Medical Center, Hyogo, Japan.

Anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis is a type of immune-mediated encephalitis, which is a new category of treatment-responsive paraneoplastic encephalitis. In patients with this disease, electroencephalography (EEG) shows non-specific findings, but recently, a unique EEG pattern, named the extreme delta brush, was detected in 40% of adult patients and was suggested to be specific to this type of encephalitis. Here, we describe a two-year-old boy with anti-NMDAR encephalitis, who presented with speech arrest and disturbances of gait and cognition several weeks after developing febrile convulsions. In the early stages of the disease, EEG showed 14-16 Hz, continuous, fast waves characterized by a high amplitude (200-500 µV), very diffuse spreading, and a sharp morphology, during light sleep only, which was compatible with extreme spindles. As the patient's symptoms worsened, this finding was replaced by rhythmic, diffuse, high-voltage, slow waves. Immediately after immunomodulatory therapies, including intravenous methylprednisolone and immunoglobulin, his clinical manifestations and EEG abnormalities appeared to improve. We propose that although the extreme spindle is a non-specific finding of this type of encephalitis, early EEG monitoring might be necessary to detect not only the extreme delta brush pattern, but also non-specific findings, including extreme spindles, which would aid early diagnosis and treatment.
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http://dx.doi.org/10.1016/j.braindev.2018.09.001DOI Listing
February 2019

Williams-Beuren Syndrome as a Potential Risk Factor for Burkitt Lymphoma.

Front Genet 2018 4;9:368. Epub 2018 Sep 4.

Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Williams-Beuren syndrome (WBS) is a multisystemic neurodevelopmental disorder caused by a hemizygous deletion on chromosome 7q11.23. Though at present there is a limited number of reports on WBS patients with tumors, most cases are related to blood cancer in children with WBS. We describe a case of Burkitt lymphoma in a 21-year-old man with WBS. In addition to providing a summary of published reports describing tumors observed in patients with WBS, we present a hypothesis about a possible mechanism of oncogenesis. In particular, we identified some significantly dysregulated cancer-related genes using blood samples from this patient at the age of 19 years (who have not yet developed Burkitt lymphoma). Our findings may provide a new perspective on the relation between WBS and Burkitt lymphoma.
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http://dx.doi.org/10.3389/fgene.2018.00368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6131482PMC
September 2018

Ventricular wall stress and silent myocardial damage are associated with pulse pressure in the general population.

J Clin Hypertens (Greenwich) 2018 09 23;20(9):1319-1326. Epub 2018 Jul 23.

Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan.

Pulse pressure (PP) is a risk factor for cardiovascular diseases and is associated with increased afterload and myocardial oxygen demand. Brain natriuretic peptide (BNP) and heart-type fatty acid-binding protein (H-FABP) are known as biomarkers indicating ventricular wall stress and silent myocardial damage. However, the association between PP and ventricular wall stress and silent myocardial damage in the general population is unclear. The authors enrolled 3504 patients who participated in a community-based annual health check. Serum levels of BNP and H-FABP were measured as markers of ventricular wall stress and silent myocardial damage. Patients were divided into four groups according to the quartiles of PP. Patients in the highest PP group showed higher serum BNP and H-FABP levels than that of the other groups. Multivariate logistic analysis showed that high PP was independently associated with ventricular wall stress and silent myocardial damage on the basis of BNP and H-FABP levels. Compared with systolic blood pressure, diastolic blood pressure, and mean blood pressure, PP was superior in predicting ventricular wall stress and silent myocardial damage evaluated according to BNP and H-FABP levels, which was reflected by the receiver operating characteristic analysis. Screening of healthy patients revealed that high PP was related to high BNP and H-FABP levels, suggesting that an asymptomatic general population with high PP may be exposed to ventricular wall stress and myocardial damage and might be susceptible to silent heart failure.
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http://dx.doi.org/10.1111/jch.13349DOI Listing
September 2018

Shunt Intervention for Possible Idiopathic Normal Pressure Hydrocephalus Improves Patient Outcomes: A Nationwide Hospital-Based Survey in Japan.

Front Neurol 2018 7;9:421. Epub 2018 Jun 7.

Department of Neurosurgery, Faculty of Medicine, Juntendo University, Tokyo, Japan.

This study aimed to investigate the efficacy of cerebrospinal fluid shunt intervention for idiopathic normal pressure hydrocephalus (iNPH) using data from a nationwide epidemiological survey in Japan. We conducted a cross-sectional study using data from a nationwide epidemiological survey performed in Japan. Propensity score matching was used to select 874 patients from 1,423 patients aged ≥60 years, who were diagnosed with iNPH based on clinical guidelines following a hospital visit in 2012. Patients who experienced an improvement of at least 1 modified Rankin Scale (mRS) grade after the intervention were classified as "improved," while the remaining patients were classified as "non-improved." In the shunt intervention ( = 437) and non-shunt intervention ( = 437) groups, the differences in mRS grade improvement were analyzed using the Mann-Whitney -test. Finally, we examined subjects in the shunt intervention group ( = 974) to compare the outcomes and complications of ventriculoperitoneal (VP) shunt (n = 417) with lumboperitoneal (LP) shunt ( = 540). We examined subjects with iNPH to compare the non-shunt intervention group to the shunt intervention group following adjustment for age and mRS grade at baseline by propensity score matching (0.31-0.901). The mRS grade (mean [SD]) was found to improve with non-shunt intervention (2.46 [0.88]) and shunt intervention (1.93 [0.93]) ( < 0.001) in iNPH patients. The mRS outcome score and complications comparison between the VP and LP shunt groups did not show significant difference. In this study, analysis of the efficacy of shunts for possible iNPH conducted in Japan indicated a significant improvement in the mRS grade between baseline and outcome within 1 year, regardless of the surgical technique, and shunt intervention was found to be effective.
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http://dx.doi.org/10.3389/fneur.2018.00421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6004916PMC
June 2018

p.G376D mutation, found in rapid progressive familial ALS, induces mislocalization of TDP-43.

eNeurologicalSci 2018 Jun 12;11:20-22. Epub 2018 Apr 12.

Department of Neurology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.

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http://dx.doi.org/10.1016/j.ensci.2018.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006914PMC
June 2018

Impact of cigarette smoking on decline in forced expiratory volume in 1s relative to severity of airflow obstruction in a Japanese general population: The Yamagata-Takahata study.

Respir Investig 2018 Mar 24;56(2):120-127. Epub 2017 Dec 24.

Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan. Electronic address:

Background: Few studies are available regarding the annual decline of forced expiratory volume in 1s (FEV1) in chronic obstructive pulmonary disease patients with mild airflow obstruction. This study sought to clarify to what extent cigarette-smoking individuals with mild airflow obstruction lose pulmonary function annually.

Methods: From 2004 to 2006, pulmonary function tests were performed on people >40 years of age, during the annual health checkup held in Takahata, Yamagata, Japan (initial study population, n=3253). In 2011, pulmonary function tests were performed again on participants who agreed to undergo reexamination (follow-up study population, n=838).

Results: Smokers have decreased pulmonary function in terms of percent forced vital capacity (FVC), %FEV1, and FEV1/FVC; the stages of airflow obstruction were also more severe in smokers than never-smokers. The annual decline in FEV1 was significantly greater in smokers than in never-smokers. The median annual decline in FEV1 was most significant in individuals with mild airflow obstruction. The annual decline in FEV1 was greater in smokers with mild airflow obstruction than in smokers with moderate airflow obstruction. In analyzing the decline in %FEV1, the annual change in smokers with mild airflow obstruction was greater than that in smokers with normal spirometric values.

Conclusion: The annual decline in FEV1 was most significant in smokers with mild airflow obstruction in a Japanese general population. This highlights the importance of early detection of chronic obstructive pulmonary disease patients among the general population in order to prevent disease progression in undiagnosed patients.
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http://dx.doi.org/10.1016/j.resinv.2017.11.011DOI Listing
March 2018

Prevalence of diabetes mellitus in individuals with airflow obstruction in a Japanese general population: The Yamagata-Takahata Study.

Respir Investig 2018 Jan 7;56(1):34-39. Epub 2017 Dec 7.

Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan. Electronic address:

Background: Diabetes has been reported as a comorbidity of chronic obstructive pulmonary disease (COPD) in Western countries, but it has not been demonstrated in epidemiological reports in Japan. The purpose of this study was to clarify whether the relationship between airflow obstruction and diabetes can be confirmed in a Japanese general population.

Methods: From 2004 to 2006, blood sampling and pulmonary function tests were performed on 3045 people over the age of 40 years in annual health check-ups held in Takahata, Yamagata Prefecture, Japan. Pulmonary function was re-evaluated in 2009 and 2011.

Results: The prevalence of diabetes did not differ between subjects with and without airflow obstruction. Furthermore, although body mass index decreased, no increase in the prevalence of diabetes was observed with the progression of airflow obstruction. The annual changes in forced expiration volume in 1s (FEV1) did not differ depending on the presence or absence of diabetes in the study population.

Conclusion: There was no difference in the prevalence of diabetes between subjects with airflow obstruction and those without. As patients with COPD in Japan are thinner than in the West, diabetes may not be a common comorbidity in Japanese patients with COPD.
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http://dx.doi.org/10.1016/j.resinv.2017.11.003DOI Listing
January 2018

Gender differences in the impact of anemia on subclinical myocardial damage and cardiovascular mortality in the general population: The Yamagata (Takahata) study.

Int J Cardiol 2018 Feb 10;252:207-212. Epub 2017 Nov 10.

Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan.

Background: Anemia has been shown to worsen cardiovascular diseases. However, it is unclear whether there is a gender difference in the impact of anemia on subclinical myocardial damage and cardiovascular mortality in the general population.

Methods: A prospective cohort study was conducted in a community based on annual health checks. Serum heart-type fatty acid binding protein (H-FABP) levels, which is a marker for myocardial damage, and blood counts were measured at baseline in subjects without previous cardiovascular diseases (n=3111).

Results: There were 343 subjects (11.0%) with anemia at baseline. H-FABP levels were inversely correlated with hemoglobin concentrations in male subjects, whereas there was no such correlation in female subjects, irrespective of the status of menopause. Prevalence of myocardial damage (H-FABP ≥4.3ng/ml) was significantly higher in male subjects with anemia than those without, irrespective of the type of anemia (microcytic, normocytic, and macrocytic). Multivariate logistic regression analysis revealed that anemia was an independent predictor of myocardial damage after adjusting for confounders. During 10years of follow-up, there were 204 all-cause deaths including 57 cardiovascular deaths. Kaplan-Meier analysis demonstrated that cardiovascular mortality was higher in male subjects with anemia than in those without. However, anemia was not associated with cardiovascular mortality in female subjects. Multivariate Cox proportional hazard analysis revealed that anemia was an independent predictor of all-cause and cardiovascular mortalities after adjusting for confounders.

Conclusion: Anemia was an independent predictor of all-cause and cardiovascular mortalities, and subclinical myocardial damage in male subjects, but not in female subjects.
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http://dx.doi.org/10.1016/j.ijcard.2017.11.019DOI Listing
February 2018

Cross-Sectional and Longitudinal Investigation of the Power Vector in Astigmatism: The Yamagata Study (Funagata).

Cornea 2018 Jan;37(1):53-58

Advanced Cancer Science, Faculty of Medicine, Yamagata University, Yamagata, Japan.

Purpose: To investigate how age and other factors affect astigmatism in Japanese adults over a period of 5 years.

Methods: We included 512 Japanese participants who had undergone systemic and ophthalmological examinations both in 2005-2007 and in 2010-2012 in Funagata town, Yamagata, Japan. Astigmatism was evaluated using power vector analyses, where J0 represents the power of orthogonal astigmatism. Positive values of J0 indicate with-the-rule astigmatism, whereas negative values indicate against-the-rule (ATR).

Results: In this cross-sectional investigation, J0 represented the power of orthogonal astigmatism, and multivariate regression revealed that both J0 and corneal J0 (cJ0) declined with increasing age (both P < 0.001). In a longitudinal investigation spanning 5 years, the mean amounts of change (Δ) in J0 and ΔcJ0 were -0.045 ± 0.308 and -0.072 ± 0.278, respectively. This confirmed an ATR shift with increasing age in most individuals. The age-divided distribution of the magnitude of differences indicated that older age was associated with a larger astigmatic change over a 5-year period in both the cornea and the entire eye. Using multivariate logistic regression, we observed that older age at baseline was a risk factor for low ΔJ0, indicating a large shift toward ATR astigmatism.

Conclusions: We confirmed that a refractive and keratometric shift toward ATR astigmatism occurs with aging. Older age at baseline was also associated with a larger magnitude of astigmatic changes over the subsequent 5 years.
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http://dx.doi.org/10.1097/ICO.0000000000001418DOI Listing
January 2018

Superficial Siderosis Associated with a Spinal Dural Defect.

Magn Reson Med Sci 2018 07 3;17(3):189-190. Epub 2017 Oct 3.

Department of Diagnostic Radiology, Yamagata University Faculty of Medicine.

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http://dx.doi.org/10.2463/mrms.ci.2017-0043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6039777PMC
July 2018