研究者詳細 - 三村　将

論文 - 三村　将

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Increased blood COASY DNA methylation levels a potential biomarker for early pathology of Alzheimer’s disease

Kobayashi N., Shinagawa S., Niimura H., Kida H., Nagata T., Tagai K., Shimada K., Oka N., Shikimoto R., Noda Y., Nakajima S., Mimura M., Shigeta M., Kondo K.

Scientific Reports （Scientific Reports） 10 （ 1 ） 2020年12月

© 2020, The Author(s). Early diagnosis of dementia including Alzheimer’s disease (AD) is an urgent medical and welfare issue. However, to date, no simple biometrics have been available. We reported that blood DNA methylation levels of the COASY gene, which encodes coenzyme A synthase, were increased in individuals with AD and amnestic mild cognitive impairment (aMCI). The present study sought to replicate these findings with larger numbers of samples. Another objective was to clarify whether COASY methylation is associated with neurodegeneration through a comparison of AD, AD with cardiovascular disease (CVD), and vascular dementia (VaD). We measured blood COASY methylation levels in normal controls (NCs) (n = 200), and individuals with aMCI (n = 22), AD (n = 151), and VaD (n = 21). Compared with NCs, they were significantly higher in individuals with aMCI and AD. Further, they were significantly higher in AD patients without cardiovascular diseases compared to AD patients with them. These findings suggest that COASY methylation levels may be related to neurodegeneration in AD.

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Study design and baseline characteristics of a population-based prospective cohort study of dementia in Japan: the Japan Prospective Studies Collaboration for Aging and Dementia (JPSC-AD)

Ninomiya T., Nakaji S., Maeda T., Yamada M., Mimura M., Nakashima K., Mori T., Takebayashi M., Ohara T., Hata J., Kokubo Y., Uchida K., Taki Y., Kumagai S., Yonemoto K., Yoshida H., Muto K., Momozawa Y., Akiyama M., Kubo M., Ikeda M., Kanba S., Kiyohara Y., Ninomiya T., Shibata M., Yoshida D., Hirakawa Y., Honda T., Chen S., Hirabayashi N., Furuta Y., Mihara A., Nakazawa T., Ohara T., Ihara K., Murashita K., Sawada K., Jung S., Terayama Y., Yonezawa H., Takahashi J., Akasaka H., Noguchi-Shinohara M., Iwasa K., Sakai K., Hayashi K., Niimura H., Shikimoto R., Kida H., Eguchi Y., Fukada Y., Kowa H., Wada K., Kishi M., Yoshida T., Shimizu H., Tachibana A., Ueno S.i., Ishikawa T., Fukuhara R., Koyama A., Hashimoto M., Esaki M., Takano Y., Inoue Y.

Environmental Health and Preventive Medicine （Environmental Health and Preventive Medicine） 25 （ 1 ） 2020年12月

ISSN 1342078X

© 2020, The Author(s). Background: The burden of dementia is growing rapidly and has become a medical and social problem in Japan. Prospective cohort studies have been considered an effective methodology to clarify the risk factors and the etiology of dementia. We aimed to perform a large-scale dementia cohort study to elucidate environmental and genetic risk factors for dementia, as well as their interaction. Methods: The Japan Prospective Studies Collaboration for Aging and Dementia (JPSC-AD) is a multisite, population-based prospective cohort study of dementia, which was designed to enroll approximately 10,000 community-dwelling residents aged 65 years or older from 8 sites in Japan and to follow them up prospectively for at least 5 years. Baseline exposure data, including lifestyles, medical information, diets, physical activities, blood pressure, cognitive function, blood test, brain magnetic resonance imaging (MRI), and DNA samples, were collected with a pre-specified protocol and standardized measurement methods. The primary outcome was the development of dementia and its subtypes. The diagnosis of dementia was adjudicated by an endpoint adjudication committee using standard criteria and clinical information according to the Diagnostic and Statistical Manual of Mental Disorders, 3rd Revised Edition. For brain MRI, three-dimensional acquisition of T1-weighted images was performed. Individual participant data were pooled for data analyses. Results: The baseline survey was conducted from 2016 to 2018. The follow-up surveys are ongoing. A total of 11,410 individuals aged 65 years or older participated in the study. The mean age was 74.4 years, and 41.9% were male. The prevalence of dementia at baseline was 8.5% in overall participants. However, it was 16.4% among three sites where additional home visit and/or nursing home visit surveys were performed. Approximately two-thirds of dementia cases at baseline were Alzheimer’s disease. Conclusions: The prospective cohort data from the JPSC-AD will provide valuable insights regarding the risk factors and etiology of dementia as well as for the development of predictive models and diagnostic markers for the future onset of dementia. The findings of this study will improve our understanding of dementia and provide helpful information to establish effective preventive strategies for dementia in Japan.

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Primary functional brain connections associated with melancholic major depressive disorder and modulation by antidepressants

Ichikawa N., Lisi G., Yahata N., Okada G., Takamura M., Hashimoto R.i., Yamada T., Yamada M., Suhara T., Moriguchi S., Mimura M., Yoshihara Y., Takahashi H., Kasai K., Kato N., Yamawaki S., Seymour B., Kawato M., Morimoto J., Okamoto Y.

Scientific Reports （Scientific Reports） 10 （ 1 ） 2020年12月

© 2020, The Author(s). The limited efficacy of available antidepressant therapies may be due to how they affect the underlying brain network. The purpose of this study was to develop a melancholic MDD biomarker to identify critically important functional connections (FCs), and explore their association to treatments. Resting state fMRI data of 130 individuals (65 melancholic major depressive disorder (MDD) patients, 65 healthy controls) were included to build a melancholic MDD classifier, and 10 FCs were selected by our sparse machine learning algorithm. This biomarker generalized to a drug-free independent cohort of melancholic MDD, and did not generalize to other MDD subtypes or other psychiatric disorders. Moreover, we found that antidepressants had a heterogeneous effect on the identified FCs of 25 melancholic MDDs. In particular, it did impact the FC between left dorsolateral prefrontal cortex (DLPFC)/inferior frontal gyrus (IFG) and posterior cingulate cortex (PCC)/precuneus, ranked as the second ‘most important’ FC based on the biomarker weights, whilst other eight FCs were normalized. Given that left DLPFC has been proposed as an explicit target of depression treatments, this suggest that the limited efficacy of antidepressants might be compensated by combining therapies with targeted treatment as an optimized approach in the future.

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Optimal robot for intervention for individuals with autism spectrum disorders

Kumazaki H., Muramatsu T., Yoshikawa Y., Matsumoto Y., Ishiguro H., Kikuchi M., Sumiyoshi T., Mimura M.

Psychiatry and Clinical Neurosciences （Psychiatry and Clinical Neurosciences） 74 （ 11 ） 581 - 586 2020年11月

ISSN 13231316

© 2020 The Authors. Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology With recent rapid advances in technology, human-like robots have begun functioning in a variety of ways. As increasing anecdotal evidence suggests, robots may offer many unique opportunities for helping individuals with autism spectrum disorders (ASD). Individuals with ASD often achieve a higher degree of task engagement through the interaction with robots than through interactions with human trainees. The type and form of robots to be used for individuals with ASD have been meticulously considered. Simple robots and animal robots are acceptable because of their simplicity and the ease of interesting and engaging interactions. Android robots have the benefit of the potential of generalization into daily life to some extent. Considering the affinity between robots and users is important to draw out the potential capabilities of robotic intervention to the fullest extent. In the robotic condition, factors such as the appearance, biological motion, clothes, hairstyle, and disposition are important. Many factors of a user, such as age, sex, and IQ, may also affect the affinity of individuals with ASD toward a robot. The potential end-users of this technology may be unaware or unconvinced of the potential roles of robots in ASD interventions. If trainers have extensive experience in using robots, they can identify many potential roles of robots based on their experience. To date, only a few studies have been conducted in the field of robotics for providing assistance to individuals with ASD, and future studies are needed to realize an optimal robot for this purpose.

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Lower mortality from suicidal trauma among patients with a psychiatric diagnosis upon admission: Nationwide japanese retrospective cohort study

Ishida T., Kuwahara Y., Shibahashi K., Okura Y., Sugiyama K., Hamabe Y., Mimura M., Suzuki T., Uchida H.

Psychiatry Research （Psychiatry Research） 293 2020年11月

ISSN 01651781

© 2020 Suicide and self-harm are major public health issues. Few studies have compared mortality from suicidal trauma between patients with and without contact with psychiatric services. This study aimed to compare the in-hospital mortality of suicidal trauma between patients with and without a psychiatric diagnosis upon hospital admission. Data on 15- to 90-year-old patients with suicidal trauma between 2004 and 2015 was extracted from the Japan Trauma Data Bank. In-hospital mortality were compared between patients with and without a psychiatric diagnosis. A total of 9,803 patients were included. The median age was 42 years (interquartile range: 29–59), and 5,010 patients (51.1%) were male. The most frequent method of injury was falling from a height (53.4%), followed by stabbing (32.3%) and burns (6.2%). In total, 4,878 patients (49.8%) had a psychiatric diagnosis upon admission. The proportion of patients with a psychiatric diagnosis was significantly lower among males, teenagers, and older people. In-hospital mortality was significantly lower among patients with a psychiatric diagnosis than those without (10.9%vs18.7%). Contact with psychiatric services might be protective among people with suicidal trauma. However, the proportion of psychiatric service use was generally low. These findings show the importance of delivering appropriate psychiatric services to high-risk patients.

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A multi-center, randomized controlled trial by the Integrative Management in Japan for Epidemic Disease (IMJEDI study-RCT) on the use of Kampo medicine, kakkonto with shosaikotokakikyosekko, in mild-To-moderate COVID-19 patients for symptomatic relief and prevention of severe stage: A structured summary of a study protocol for a randomized controlled trial

Takayama S., Namiki T., Ito T., Arita R., Nakae H., Kobayashi S., Yoshino T., Ishigami T., Tanaka K., Kainuma M., Nochioka K., Takagi A., Mimura M., Yamaguchi T., Ishii T.

Trials （Trials） 21 （ 1 ） 2020年10月

© 2020 The Author(s). Objectives: We aimed to test our hypothesis that additional administration of traditional Japanese (Kampo) medicine, kakkonto (kakkon-To: KT) and shosaikotokakikyosekko (sho-saiko-To-ka-kikyo-sekko: SSKKS), is more effective in relieving symptoms and preventing the onset of severe infection in mild-To-moderate COVID-19 patients compared to those treated only with conventional treatment. Trial design: The study is designed as a multi-center, interventional, parallel-group, randomized (1:1 ratio), investigator-sponsored, two-Arm study. Participants: Patients and inpatients will be recruited from 8 Japanese academic and non-Academic hospitals. The inclusion and exclusion criteria are as follows: Inclusion criteria: 1. Diagnosed as positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 2. Clinical stages of mild-To-moderate COVID-19 3. Symptomatic 4. ≥ 20 years of age 5. Male or female 6. Ability to communicate in Japanese 7. Outpatients and inpatients 8. Provided informed consent Exclusion criteria: 1. Difficulty in providing informed consent due to dementia, psychosis, or psychiatric symptoms 2. Allergic to Kampo or Western medicines used in this study 3. Pregnant and lactating 4. Unable to follow up 5. Participating in another clinical trial or interventional study 6. Hypokalemic or taking oral furosemide or steroids 7. Determined unsuitable for this study by the physician Intervention and comparator: Patients in the control group will receive conventional treatment with antipyretics, painkillers, or antitussives for symptoms that occurred after they contracted the SARS-CoV-2 infection. Patients in the Kampo group will receive 2.5 g of KT (TJ-1@TSUMURA and Co.) and 2.5 g of SSKKS (TJ-109@TSUMURA and Co.) 3 times a day, orally, for 14 days in addition to the conventional treatment as mentioned above. Main outcomes: The number of days till at least one of the symptoms (fever, cough, sputum, malaise, shortness of breath) improves in the first 14 days of treatment. To assess the cough, sputum, malaise, and shortness of breath, a numeric rating scale will be used to define improvement in terms of a 2-point decrease in the number of days from the start of treatment for at least 2 days. Fever will be defined as an improvement when the temperature is less than 37 °C. Randomization: Patients are randomized (1:1 ratio) to each group using the minimization method, with balancing of the arms with severity of disease stage and patient age (< 65, 65 to < 75, or ≥ 75 years). Computer-generated random numbers will be used for the minimization method. Blinding (masking): Open-label with no blinding Numbers to be randomized (sample size): The main research hypothesis of this study is that the combination of Kampo medicine and conventional treatment will significantly improve the patients' symptoms (fever, fatigue, cough, sputum, and shortness of breath) during the first 14 days of treatment as compared with conventional treatment alone. Concerning the analysis of the primary endpoint, the duration of time before improvement of at least one of the common cold-like symptoms (fever, malaise, cough, sputum, and shortness of breath) will be estimated using the Kaplan-Meier method, and the survival curves will be compared between groups using the log-rank test. Assuming this method of analysis and based on previous studies reporting the efficacy of Kampo medicine for COVID-19 and H1N1 influenza patients, the median survival time in the Kampo medicine group is estimated as 3 days; this time will be 1.5 times longer in the control group. Assuming a one-sided significance level of 5%, a power of 70%, and an allocation ratio of 1:1, the required sample size is calculated as 126 cases. To compensate for a loss in follow-up, we plan to include 150 cases in both groups (Kampo group = 75, control group = 75). Trial status: Protocol version 1.2 as of August 20, 2020 Recruitment start (expected): October 1, 2020 Recruitment finish (expected): October 31, 2023 Trial registration: Japan Registry of Clinical Trials (jRCT) jRCTs021200020. Registered on August 25, 2020 Full protocol: The full protocol is attached as an additional file and is accessible from the Trials website (Additional file 1). In the interest of expediting the dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

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Gap between patients with schizophrenia and their psychiatrists on the needs to psychopharmacological treatment: A cross-sectional study

Takahashi K., Yamazawa R., Suzuki T., Mimura M., Uchida H.

Neuropsychopharmacology Reports （Neuropsychopharmacology Reports） 40 （ 3 ） 232 - 238 2020年09月

© 2020 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Society of NeuropsychoPharmacology. Aim: Psychopharmacological treatment is indispensable in patients with schizophrenia but data on needs, preferences, and complaints about their medications are limited. Moreover, there has been no study to assess the degree of awareness of their psychiatrists (gap in needs) regarding these issues. Methods: Ninety-seven Japanese patients with schizophrenia (ICD-10) were asked to fill in the questionnaire consisting of multiple-choice questions regarding (a) their needs and complaints about psychopharmacological treatment that they were receiving, and (b) their preference of dosage form, dosing frequency, and timing of dosing. Additionally, their psychiatrists in charge were asked to predict their patients’ response to the above questions. Results: Both the most frequently endorsed need and complaints about the current psychopharmacological treatment were “nothing in particular” (n = 14, 16.7% and n = 17, 20.2%); merely 23.1% and 15.4% of their psychiatrists correctly predicted these responses, respectively. “Once a day” (n = 56, 65.1%), “at bedtime” (n = 53, 61.6%), and “tablet” (n = 51, 59.3%) were the patients’ most favorite dosing frequency, timing, and dosage form, respectively; 59.8% (n = 49), 54.9% (n = 45), and 64.6% (n = 53) of their psychiatrists predicted them. Conclusions: These findings suggest that there is substantial room for improvement on the side of psychiatrists to capture their patients’ needs and complaints about psychopharmacological treatment.

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Prescription patterns of psychotropics in patients receiving synthetic glucocorticoids

Yatomi T., Uchida T., Takeuchi H., Kuramochi S., Yoshimura K., Mimura M., Uchida H.

Acta Psychiatrica Scandinavica （Acta Psychiatrica Scandinavica） 142 （ 3 ） 242 - 248 2020年09月

ISSN 0001690X

© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Objective: Synthetic glucocorticoids cause various psychiatric symptoms. Prescription of psychotropic drugs could be considered to be a proxy for manifestation of psychiatric symptoms. The aim of this study was to investigate the prescriptions of psychotropics in outpatients receiving synthetic glucocorticoids. Methods: We used the claims sampling data during January 2015 from the National Database of Health Insurance Claims and Specific Health Checkups of Japan made by the Ministry of Health, Labor, and Welfare in Japan. We compared the prescription rates of psychotropics between outpatients receiving oral synthetic glucocorticoids and age- and sex-matched controls and the prescription rates of psychotropics among the eight dosage groups of synthetic glucocorticoids by chi-squared test, and chlorpromazine/imipramine/diazepam equivalent doses (or daily defined doses) of respective psychotropics among these groups using Welch's t-test. Results: Synthetic glucocorticoids were prescribed to 3.1% (n = 18 122) of 581 990 patients. The prescription rates of psychotropics were significantly higher among the synthetic glucocorticoid recipients than among the non-recipients: antipsychotics, 1.8% (n = 321) vs. 1.1% (n = 201) (P = 1.4 × 10−7); antidepressants, 4.0% (n = 724) vs. 2.0% (n = 359) (P = 8.7 × 10−30); anxiolytics/hypnotics, 16.7% (n = 3029) vs. 10.2% (n = 1841) (P = 2.7 × 10−75); and mood stabilizers, 1.3% (n = 238) vs. 0.7% (n = 120) (P = 3.6 × 10−10) respectively. There was no significant difference in the prescription rates of any psychotropic drugs, other than anxiolytics/hypnotics, among the eight synthetic glucocorticoid dosage groups. Conclusion: Prescriptions of oral synthetic glucocorticoids were found to be associated with the use of any of the types of psychotropic drugs, other than anxiolytics/hypnotics, although a causal relationship could not be confirmed due to the retrospective and cross-sectional nature of this study.

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Machine-learning approach to predict on-road driving ability in healthy older people

Yamamoto Y., Hirano J., Yoshitake H., Negishi K., Mimura M., Shino M., Yamagata B.

Psychiatry and Clinical Neurosciences （Psychiatry and Clinical Neurosciences） 74 （ 9 ） 488 - 495 2020年09月

ISSN 13231316

© 2020 The Authors Psychiatry and Clinical Neurosciences © 2020 Japanese Society of Psychiatry and Neurology Aim: In Japan, fatal traffic accidents due to older drivers are on the rise. Considering that approximately half the older drivers who have caused fatal accidents are cognitively normal healthy people, it has been required to detect older drivers who are cognitively normal but at high risk of having fatal traffic accidents. However, a standardized method for assessing the driving ability of older drivers has not yet been established. We thus aimed to identify a new sensing method for the evaluation of the on-road driving ability of healthy older people on the basis of vehicle behaviors. Methods: We enrolled 33 healthy older individuals aged over 65 years and utilized a machine-learning approach to dissociate unsafe drivers from safe drivers based on cognitive assessments and a functional visual acuity test. Results: The linear support vector machine classifier successfully dissociated unsafe drivers from safe drivers with accuracy of 84.8% (sensitivity of 66.7% and specificity of 95.2%). Five clinical parameters, namely age, the first trial of the Rey Auditory Verbal Learning Test immediate recall, the delayed recall of the Rey–Osterrieth Complex Figure Test, the result of the free-drawn Clock Drawing Test, and maximal visual acuity, were consistently selected as essential features for the best classification model. Conclusion: Our findings improve our understanding of clinical risk factors leading to unsafe driving and may provide insight into a new intervention that prevents fatal traffic accidents caused by healthy older people.

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Using speech recognition technology to investigate the association between timing-related speech features and depression severity

Yamamoto M., Takamiya A., Sawada K., Yoshimura M., Kitazawa M., Liang K.C., Fujita T., Mimura M., Kishimoto T.

PLoS ONE （PLoS ONE） 15 （ 9 September ） 2020年09月

© 2020 Yamamoto et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background There are no reliable and validated objective biomarkers for the assessment of depression severity. We aimed to investigate the association between depression severity and timing-related speech features using speech recognition technology. Method Patients with major depressive disorder (MDD), those with bipolar disorder (BP), and healthy controls (HC) were asked to engage in a non-structured interview with research psychologists. Using automated speech recognition technology, we measured three timing-related speech features: speech rate, pause time, and response time. The severity of depression was assessed using the Hamilton Depression Rating Scale 17-item version (HAMD-17). We conducted the current study to answer the following questions: 1) Are there differences in speech features among MDD, BP, and HC? 2) Do speech features correlate with depression severity? 3) Do changes in speech features correlate with within-subject changes in depression severity? Results We collected 1058 data sets from 241 individuals for the study (97 MDD, 68 BP, and 76 HC). There were significant differences in speech features among groups; depressed patients showed slower speech rate, longer pause time, and longer response time than HC. All timing-related speech features showed significant associations with HAMD-17 total scores. Longitudinal changes in speech rate correlated with changes in HAMD-17 total scores. Conclusions Depressed individuals showed longer response time, longer pause time, and slower speech rate than healthy individuals, all of which were suggestive of psychomotor retardation. Our study suggests that speech features could be used as objective biomarkers for the assessment of depression severity.

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Resting-state isolated effective connectivity of the cingulate cortex as a neurophysiological biomarker in patients with severe treatment-resistant schizophrenia

Wada M., Nakajima S., Tarumi R., Masuda F., Miyazaki T., Tsugawa S., Ogyu K., Honda S., Matsushita K., Kikuchi Y., Fujii S., Blumberger D.M., Daskalakis Z.J., Mimura M., Noda Y.

Journal of Personalized Medicine （Journal of Personalized Medicine） 10 （ 3 ） 1 - 12 2020年09月

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. Background: The neural basis of treatment-resistant schizophrenia (TRS) remains unclear. Previous neuroimaging studies suggest that aberrant connectivity between the anterior cingulate cortex (ACC) and default mode network (DMN) may play a key role in the pathophysiology of TRS. Thus, we aimed to examine the connectivity between the ACC and posterior cingulate cortex (PCC), a hub of the DMN, computing isolated effective coherence (iCoh), which represents causal effective connectivity. Methods: Resting-state electroencephalogram with 19 channels was acquired from seventeen patients with TRS and thirty patients with non-TRS (nTRS). The iCoh values between the PCC and ACC were calculated using sLORETA software. We conducted four-way analyses of variance (ANOVAs) for iCoh values with group as a between-subject factor and frequency, directionality, and laterality as within-subject factors and post-hoc independent t-tests. Results: The ANOVA and post-hoc t-tests for the iCoh ratio of directionality from PCC to ACC showed significant findings in delta (t45 = 7.659, p = 0.008) and theta (t45 = 8.066, p = 0.007) bands in the left side (TRS < nTRS). Conclusion: Left delta and theta PCC and ACC iCoh ratio may represent a neurophysiological basis of TRS. Given the preliminary nature of this study, these results warrant further study to confirm the importance of iCoh as a clinical indicator for treatment-resistance.

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The project for objective measures using computational psychiatry technology (PROMPT): Rationale, design, and methodology

Kishimoto T., Takamiya A., Liang K.c., Funaki K., Fujita T., Kitazawa M., Yoshimura M., Tazawa Y., Horigome T., Eguchi Y., Kikuchi T., Tomita M., Bun S., Murakami J., Sumali B., Warnita T., Kishi A., Yotsui M., Toyoshiba H., Mitsukura Y., Shinoda K., Sakakibara Y., Mimura M.

Contemporary Clinical Trials Communications （Contemporary Clinical Trials Communications） 19 2020年09月

ISSN 24518654

© 2020 The Authors Introduction: Depressive and neurocognitive disorders are debilitating conditions that account for the leading causes of years lived with disability worldwide. However, there are no biomarkers that are objective or easy-to-obtain in daily clinical practice, which leads to difficulties in assessing treatment response and developing new drugs. New technology allows quantification of features that clinicians perceive as reflective of disorder severity, such as facial expressions, phonic/speech information, body motion, daily activity, and sleep. Methods: Major depressive disorder, bipolar disorder, and major and minor neurocognitive disorders as well as healthy controls are recruited for the study. A psychiatrist/psychologist conducts conversational 10-min interviews with participants ≤10 times within up to five years of follow-up. Interviews are recorded using RGB and infrared cameras, and an array microphone. As an option, participants are asked to wear wrist-band type devices during the observational period. Various software is used to process the raw video, voice, infrared, and wearable device data. A machine learning approach is used to predict the presence of symptoms, severity, and the improvement/deterioration of symptoms. Discussion: The overall goal of this proposed study, the Project for Objective Measures Using Computational Psychiatry Technology (PROMPT), is to develop objective, noninvasive, and easy-to-use biomarkers for assessing the severity of depressive and neurocognitive disorders in the hopes of guiding decision-making in clinical settings as well as reducing the risk of clinical trial failure. Challenges may include the large variability of samples, which makes it difficult to extract the features that commonly reflect disorder severity. Trial Registration: UMIN000021396, University Hospital Medical Information Network (UMIN).

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Increasing light physical activity helps to maintain cognitive function among the community-dwelling oldest old population: a cross-sectional study using actigraph from the Arakawa 85+ study

Suzuki K., Niimura H., Kida H., Eguchi Y., Kitashima C., Takayama M., Mimura M.

Geriatrics and Gerontology International （Geriatrics and Gerontology International） 20 （ 8 ） 773 - 778 2020年08月

ISSN 14441586

© 2020 Japan Geriatrics Society Aim: To investigate the influence of replacing sedentary time with physical activity on cognitive function using an isotemporal substitution model in a population of community-dwelling oldest old. Methods: This cross-sectional study included residents of the Arakawa ward, Tokyo, who were part of a prospective cohort from the Arakawa 85+ study. We measured physical activity in 136 participants using a triaxial actigraph. Cognitive function was measured using the Addenbrooke's Cognitive Examination-III and participants were divided into a “cognitive decline group” (Addenbrooke's Cognitive Examination-III ≤88) and “cognitive maintain group” (Addenbrooke's Cognitive Examination-III ≥89). Physical activity was divided into three categories: sedentary behavior (≤1.5 metabolic equivalents), light physical activity (>1.5 to <3.0 metabolic equivalents), and moderate-to-vigorous physical activity (≥3 metabolic equivalents). Using an isotemporal substitution approach, we applied multiple logistic regression analysis to demonstrate the association between cognitive function and replacing 30 min/day of sedentary behavior with an equal period of light physical activity. Covariates included age, education and the Center for Epidemiologic Studies Depression Scale. Results: Our findings showed that in men, replacing 30 min of sedentary behavior per day with light physical activity was associated with a 1.47-fold increase in the odds of maintaining cognitive function. An association between physical activity and cognitive function was not observed in female participants. Conclusions: Our results indicate that substituting sedentary behavior with light physical activity could be helpful in maintaining cognitive function in community-dwelling oldest old men. These results highlight the importance of behavioral changes to promote cognition. Geriatr Gerontol Int 2020; 20: 773–778.

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Remote neuropsychological assessment of elderly Japanese population using the Alzheimer’s Disease Assessment Scale: A validation study

Yoshida K., Yamaoka Y., Eguchi Y., Sato D., Iiboshi K., Kishimoto M., Mimura M., Kishimoto T.

Journal of Telemedicine and Telecare （Journal of Telemedicine and Telecare） 26 （ 7-8 ） 482 - 487 2020年08月

ISSN 1357633X

© The Author(s) 2019. Introduction: Studies have demonstrated the high agreement of several remote neuropsychological tests using video teleconferencing (VTC) with face-to-face (FTF) tests. However, the reliability of the remotely administered Alzheimer’s Disease Assessment Scale cognitive subscale (ADAS-cog), one of the most commonly used neuropsychological tests to detect cognitive decline, has not been substantially elucidated, particularly in Japanese populations. Therefore, this study aimed to evaluate the reliability of the remotely administered ADAS-cog compared with FTF-administered ADAS-cog among elderly Japanese participants. Methods: Participants aged ≥60 years with and without cognitive impairment, i.e. those with mild cognitive impairment (MCI), those with dementia and healthy controls (HCs), were assessed with the ADAS-cog using VTC and FTF testing at an interval of >2 weeks and <3 months. The assessment order (VTC or FTF) was randomized by participants. Participants’ scores were compared among the entire sample, as well as subgroups, using intra-class correlation coefficients (ICCs) in a mixed-effects model. Results: A total of 73 participants were included in the study (36 men; age, 76.3 ± 7.6 years). The ICC for the ADAS-cog total score was high in the entire sample (0.86), whereas ICCs were moderate to high for the subgroups (MCI: 0.63, dementia: 0.80 and HC: 0.74). Discussion: The results indicate that a VTC-administered ADAS-cog could be an alternative for an FTF-administered ADAS-cog, although further replication studies with larger sample sizes and a wider range of cognitive functionalities are warranted.

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Dissociation in Pharmacokinetic Attenuation Between Central Dopamine D2 Receptor Occupancy and Peripheral Blood Concentration of Antipsychotics: A Systematic Review

Kurose S., Mimura Y., Uchida H., Takahata K., Kim E., Suzuki T., Mimura M., Takeuchi H.

The Journal of clinical psychiatry （The Journal of clinical psychiatry） 81 （ 5 ） 2020年07月

© Copyright 2020 Physicians Postgraduate Press, Inc. OBJECTIVE: The objective of this study was to examine the extent of possible dissociation in pharmacokinetic decay between central dopamine D₂ receptor occupancy with antipsychotics and their peripheral blood concentrations. DATA SOURCES: MEDLINE and Embase were searched using the following keywords: (positron emission tomography OR PET OR single-photon emission computed tomography OR SPECT) AND (dopamine OR D2) AND (receptor* OR occupanc*) AND antipsychotic*, with a limitation of English language (last search: December 14, 2019). STUDY SELECTION: The search identified 18 studies that met the following criteria: (1) including patients with schizophrenia spectrum disorders and/or healthy subjects, (2) using positron emission tomography or single-photon emission computed tomography, and (3) examining the time courses of D₂ occupancy with antipsychotics and their blood concentrations. DATA EXTRACTION: The ratios of D₂ occupancy reduction rate (%) from peak to blood concentration reduction rate (%) from peak (relative attenuation ratio) were calculated. RESULTS: Among the studies, oral risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, perospirone, haloperidol, sulpiride, and clozapine and long-acting injectable risperidone and haloperidol were included. Relative attenuation ratios were less than 1, indicating a slower central versus peripheral attenuation, across the time points for all antipsychotic types and doses with only a few exceptions. The ratio decreased in a dose-dependent as well as a peak D₂ occupancy-dependent fashion. It contrarily increased in a time-dependent manner. CONCLUSIONS: The findings indicate pharmacokinetic attenuation of antipsychotics was generally slower at the central versus the peripheral level and pose a critical challenge to the current dosing strategy that primarily relies on peripheral pharmacokinetics of antipsychotics.

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Alterations of Heartbeat Evoked Magnetic Fields Induced by Sounds of Disgust

Kato Y., Takei Y., Umeda S., Mimura M., Fukuda M.

Frontiers in Psychiatry （Frontiers in Psychiatry） 11 2020年07月

© Copyright © 2020 Kato, Takei, Umeda, Mimura and Fukuda. The majority of the models of emotional processing attribute subjective emotional feelings to physiological changes in the internal milieu, which are sensed by the interoceptive system. These physiological reactions evoked by emotional phenomena occur via the autonomic nervous system, and give rise to alterations in body-mind interactions that are characterized by heartbeat evoked magnetic fields (HEFs) involving brain regions associated with emotional perception. The current study used magnetoencephalography (MEG) to examine regional cortical activity and connectivity changes in HEFs provoked by the emotion of disgust. MEG results from 39 healthy subjects (22 female) revealed that passively listening to sounds of disgust elicited right insular cortical activity and enhancement of cortical connectivity between the right anterior ventral insular cortex and left ventromedial prefrontal cortex, demonstrated by phase lag indexes in the beta frequency range. Furthermore, inter-trial coherence significantly increased at 19 Hz and 23 Hz, and decreased at 14 Hz, which highlights the involvement of low beta oscillations in emotional processing. As these results were based on spontaneously triggered bioelectrical signals, more indigenous and induced signals were extracted with a block designed experiment. The insular cortices play an important role in emotional regulation and perception as the main cortical target for signals with interoceptive information, providing direct substrates of emotional feelings. The current results provide a novel insight into frequency properties of emotional processing, and suggest that emotional arousal evoked by listening to sounds of disgust partially impact the autonomic nervous system, altering HEFs via connectivity changes in the right anterior ventral insular cortex and left ventromedial prefrontal cortex.

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A validation study of the remotely administered Montreal cognitive assessment tool in the elderly Japanese population

Iiboshi K., Yoshida K., Yamaoka Y., Eguchi Y., Sato D., Kishimoto M., Funaki K., Mimura M., Kishimoto T.

Telemedicine and e-Health （Telemedicine and e-Health） 26 （ 7 ） 1 - 9 2020年07月

ISSN 15305627

© MARY ANN LIEBERT, INC. Background: In an aging society, neuropsychological testing using video teleconferencing (VTC) is increasingly important. Despite the potential benefit of a VTC-administered Montreal Cognitive Assessment Tool (MoCA) to detect cognitive decline, only a limited number of studies have investigated this tool's reliability. Therefore, we aimed to evaluate the reliability of VTC-administered MoCA compared with face-to-face (FTF)-administered MoCA among elderly Japanese participants. Moreover, we examined participants' satisfaction with VTC-administered MoCA. Methods: Participants ‡60 years of age with and without cognitive impairment (i.e., those with mild cognitive impairment [MCI], those with dementia, and healthy controls [HC]) were assessed with VTC- and FTF-administered MoCA at an interval of >2 weeks and <3 months. The order effect (VTC first vs. FTF first) and time effect (first vs. second testing session), as well as several covariates such as age and years of education were controlled. Intraclass correlation coefficients (ICCs) were calculated using a mixed-effects model to assess the agreement between the two (VTC- vs. FTF-administered) groups. Participants' satisfaction with VTC-administered MoCA was examined using a Likert scale asking seven questions. Results: We included 73 participants in the study (36 men; age, 76.3 - 7.5 years). The ICC for the MoCA total score was high in the entire sample (0.85), whereas ICCs were moderate to high for the subgroups (MCI: 0.82, dementia: 0.82, and HC: 0.53). Furthermore, we found good overall participant satisfaction with VTC-administered MoCA. Discussion: VTC-administered MoCA appears viable as an alternative to FTF-administered MoCA, although further replication studies with larger sample sizes are needed.

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Opposing Ventral Striatal Medium Spiny Neuron Activities Shaped by Striatal Parvalbumin-Expressing Interneurons during Goal-Directed Behaviors

Yoshida K., Tsutsui-Kimura I., Kono A., Yamanaka A., Kobayashi K., Watanabe M., Mimura M., Tanaka K.F.

Cell Reports （Cell Reports） 31 （ 13 ） 2020年06月

© 2020 The Authors Medium spiny neurons (MSNs) of mice show opposing activities upon the initiation of a food-seeking lever press task. Ventromedial striatal (VMS)-MSNs are inhibited but ventrolateral striatal (VLS)-MSNs are activated; these activities mediate action selection and action initiation, respectively. To understand what input shapes the opposing MSN activities, here, we monitor cortical input activities at the cell population level and artificially reverse them. We demonstrate that the ventral hippocampus (vHP) and the insular cortex (IC) are major inputs to the VMS and VLS, both projections show silencing at the trial start time, and the vHP-VMS and IC-VLS pathways form functionally coupled input-output units during the task. Of note, the upstream IC silencing is converted to the downstream VLS-MSN activation. We find biased localization of striatal parvalbumin-expressing interneurons (PV INs) and verify PV IN-dependent feedforward architecture in the VLS. Our results reveal a distinct mode of cortico-striatal signal conveyance via feedforward disinhibition in behaving animals.

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Pharmacological management of behavioral disturbances in patients with Alzheimer’s disease

Nagata T., Shinagawa S., Nakajima S., Noda Y., Mimura M.

Expert Opinion on Pharmacotherapy （Expert Opinion on Pharmacotherapy） 21 （ 9 ） 1093 - 1102 2020年06月

ISSN 14656566

© 2020, © 2020 Informa UK Limited, trading as Taylor & Francis Group. Neuropsychiatric symptoms (NPS) inevitably occur during the course of Alzheimer’s disease (AD) including psychosis, aggression, and depression. The effectiveness of pharmacological treatments for NPS has been limited because of their lack of efficacy, discontinuation due to undesirable adverse events, or poor adherence. In recent consensus guidelines, non-pharmacological treatments for NPS have been prioritized as first-line management strategies. Pharmacological treatments for severe NPS should be administrated as a second-line approach, and have been suggested to be started at a lower dosage followed by titration to a minimum effective dosage and for a limited time period. However, recent studies have shown that some patients receiving pharmacological treatments do not exhibit treatment efficacy in comparison with placebo. The concurrence of several sub-symptoms in NPS makes it difficult to target one symptom exclusively. Therefore, the current review focuses on a strategy for such refractory NPS in patients with AD. Recent randomized controlled trials have shown that the severity of NPS gradually reduces in a time-dependent manner regardless of active treatments. Therefore, clinicians should consider potential causes of NPS sub-symptoms from multifactorial aspects and select alternative treatments (e.g. neuromodulation or relocation into specialized care units) during the long-term disease course.

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White matter microstructural organizations in patients with severe treatment-resistant schizophrenia: A diffusion tensor imaging study

Ochi R., Noda Y., Tsuchimoto S., Tarumi R., Honda S., Matsushita K., Tsugawa S., Plitman E., Masuda F., Ogyu K., Wada M., Miyazaki T., Fujii S., Chakravarty M.M., Graff-Guerrero A., Uchida H., Mimura M., Nakajima S.

Progress in Neuro-Psychopharmacology and Biological Psychiatry （Progress in Neuro-Psychopharmacology and Biological Psychiatry） 100 2020年06月

ISSN 02785846

© 2020 Elsevier Inc. Previous diffusion tensor imaging (DTI) studies have reported white matter alterations in patients with schizophrenia. Notably, one third of this population does not respond to first-line antipsychotics and is thus referred to as treatment-resistant schizophrenia (TRS). Despite potentially distinct neural bases between TRS and non-TRS, few studies have compared white matter integrity between these groups. In order to reflect clinical picture of TRS, we enrolled TRS patients who had severe symptoms. According to the consensus criteria for TRS. TRS was defined by severe positive symptomatology despite optimal antipsychotic treatment. Fractional anisotropy (FA), an index of white matter integrity, was examined by DTI and analyzed with tract-based spatial statistics in 24 TRS patients (mean PANSS = 108.9), 28 non-TRS patients (mean PANSS = 50.0), and 27 healthy controls (HCs) for group comparison. Additionally, correlation analyses were conducted between FA values and symptomatology. The TRS group had lower FA values in multiple tracts (cerebral peduncle, corona radiata, corpus callosum, external and internal capsules, posterior thalamic radiation, sagittal stratum, superior longitudinal fasciculus, tapetum, and uncinate fasciculus) compared to the HC group as well as the non-TRS group (p <.05; family-wise error-corrected), while no differences were found between the non-TRS and HC groups. In the TRS group, FA values in most of the tracts (other than the left anterior limb of internal capsule, left cerebral peduncle, and right uncinate fasciculus) were negatively correlated with the Positive and Negative Syndrome Scale total scores, and negative and general symptom scores. No such relationships were found in the non-TRS group. The identified white matter integrity deficits may reflect the pathophysiology of TRS.

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