Organized Registration for the Assessment of Dementia by the Nationwide General Consortium Toward Effective Treatment (ORANGE) Registry: Current Status and Perspectives of Mild Cognitive Impairment.

BACKGROUND: With increasingly aging societies, a comprehensive strategy for dementia research is important. The Organized Registration for the Assessment of dementia by the Nationwide General consortium toward Effective treatment (ORANGE) Registry is the first longitudinal multicenter prospective trial-ready cohort in Japan. OBJECTIVE: To establish a large cohort for use in clinical trials and research in Japan. METHODS: This registry, based on communities, hospitals, and nursing homes, covers three dementia stages (preclinical, mild cognitive impairment [MCI], and advanced dementia), and includes more than 30 hospitals. We analyzed enrollment and 1-year follow-up data for disease progression. RESULTS: There were 1450 registered patients (649 men, 801 women; mean age, 77.92±6.70 years; mean Mini-Mental State Examination [MMSE] score, 25.19±2.76). The conversion rates from MCI to dementia and MCI to normal were 14.3% and 1.1%, respectively. High Clinical Dementia Rating score (odds ratio [OR] = 11.085, 95% confidence interval [CI]:1.619-75.913, p = 0.014), low MMSE score (OR = 0.835, 95% CI: 0.761-0.917, p < 0.001), high Geriatric Depression Scale score (OR = 1.093, 95% CI: 1.005-1.189, p = 0.038), and low body mass index (OR = 0.895, 95% CI: 0.829-0.967, p = 0.005) at enrollment were significant factors for conversion. CONCLUSION: The ORANGE MCI Registry is an established registry that facilitates creation of trial-ready cohorts to accelerate promotion of clinical trials with low reversion rates as it originates from a hospital. One-year follow-up analysis suggested assessing various factors for conversion risk. Further analyses will be possible in future with registry expansion. We will continue to refine this registry, including how it can be used more efficiently.

Differences in instrumental activities of daily living between mild cognitive impairment and Alzheimer's disease: A study using a detailed executive function assessment.

AIM: Executive dysfunction is pathognomonic for dementia and impedes the activities of daily living (ADL). This study aimed to examine the relationship of dementia severity with executive dysfunction and ADL in mild cognitive impairment and dementia. METHODS: This single-center study enrolled 86 patients (men, 40; women, 46; mean age, 76.1 ± 7.5 years) referred for cognitive and physical rehabilitation between October 2015 and September 2020. The Clinical Dementia Rating (CDR) was 0.5, 1, and ≥2 in 45, 30, and 11 patients, respectively. The presence and severity of executive dysfunction were assessed using the Behavioral Assessment of the Dysexecutive Syndrome-Japanese version (BADS). The ADL and instrumental ADL (IADL) were assessed using the Barthel Index and Frenchay Activities Index (FAI), respectively. We examined the relationship between CDR severity and overall BADS profile score and its sub-items, and that between the overall BADS profile score and IADL. RESULTS: The cognitive and executive functional assessment scores differed significantly depending on the CDR severity. The CDR severity and overall BADS profile score exhibited significant correlations. The BADS found cognitive impairment in 31%, 70%, and 100% of patients with CDR0.5, CDR1, and CDR≥2, respectively. The FAI score differed according to the CDR severity in women but not in men. The overall profile and age-adjusted BADS scores were strongly correlated with the IADL in women but not in men. CONCLUSIONS: The greater the severity of executive dysfunction, the greater the difficulty in performing ADL. This effect was more pronounced in women and may predict dementia progression. Geriatr Gerontol Int 2021; 21: 1111-1117.

Possibility of Using Quantitative Assessment with the Cube Copying Test for Evaluation of Visuo-spatial Function in Patients with Alzheimer's Disease.

OBJECTIVES: The aim of this study was to investigate the clinical usefulness of the Cube Copying Test (CCT) for quantitative assessment of visuo-spatial function in patients with Alzheimer's disease (AD). METHODS: The CCT, Raven's Colored Progressive Matrices (RCPM), and other neuropsychological tests were administered to 152 AD outpatients. For the quantitative assessment of CCT, we scored the points of connection (POC) and the number of plane-drawing errors (PDE) and categorized the pattern classification (PAC). We also measured Functional Assessment Staging (FAST) to assess the severity of AD. The relationships among CCT, RCPM, and FAST were then analyzed. RESULTS: The mean POC and PDE scores were 2.7 and 3.6, respectively, and the median PAC score was 6.0. PDE and PAC showed a linear relationship, but POC and PDE, and POC and PAC did not. Each component of CCT showed a significant correlation with RCPM scores. PDE and PAC had closer correlations with RCPM scores than POC did. The PDE and PAC results were significantly different among most of the FAST stages. CONCLUSIONS: Quantitative assessment using CCT may be effective for the quick determination of the visuo-spatial function in AD patients.

Determinants and impact of physical impairment in patient-reported outcomes among older patients with type 2 diabetes mellitus in Japan.

OBJECTIVE: To investigate the predictive factors associated with physical impairment among older patients with type 2 diabetes mellitus (T2DM) in Japan and to examine the potential impact of physical impairment on patient-reported health outcomes in this population. METHODS: A cross-sectional analysis was conducted using patient-reported data from the 2012-2014 Japan National Health and Wellness Survey. Physical impairment was measured using the Physical Component Summary (PCS) score of the Short-Form 36-Item Health Survey (SF-36) three-component model (using Japanese norms). Older T2DM patients (≥65 years old; n = 1511) were dichotomized into physically impaired (PCS ≤ 25th percentile; n = 378) and non-physically impaired (PCS > 25th percentile; n = 1133). Work productivity (absenteeism, presenteeism and overall work impairment), activity impairment and healthcare resource utilization were compared between these groups. RESULTS: Age, female sex, low and high body mass index (BMI), diabetes-related complications, cardiovascular events, unawareness of having hypoglycemic events in the past 3 months, and lack of regular exercise were significant factors associated with physical impairment in multivariable analysis. The physically impaired group reported significantly more regular outpatient visits (13.48 vs. 10.16, respectively, p < .001), 1% or greater absenteeism (16.7% vs. 4.1%, p = .005), greater presenteeism (27.8% vs. 12.2%, p = .001), overall work impairment (30.0% vs. 13.0%, p = .001) and overall activity impairment (39.5% vs. 17.2%, p < .001) than the non-physically-impaired group after adjusting for covariates. CONCLUSIONS: This study identified age, BMI, diabetes-related comorbidities, history of cardiovascular events and lack of exercise as key predictors associated with physical impairment in older patients with T2DM in Japan, which predicted low work productivity as well as activity impairment. This study provides support that physical impairment in patients with T2DM may lead to low work productivity and activity impairment.Supplemental data for this article is available online at https://doi.org/10.1080/03007995.2020.1846170.

Insights into channel modulation mechanism of RYR1 mutants using Ca2+ imaging and molecular dynamics.

Type 1 ryanodine receptor (RYR1) is a Ca2+ release channel in the sarcoplasmic reticulum in skeletal muscle and plays an important role in excitation-contraction coupling. Mutations in the RYR1 gene cause severe muscle diseases such as malignant hyperthermia (MH), which is a disorder of CICR via RYR1. Thus far, >300 mutations in RYR1 have been reported in patients with MH. However, owing to a lack of comprehensive analysis of the structure-function relationship of mutant RYR1, the mechanism remains largely unknown. Here, we combined functional studies and molecular dynamics (MD) simulations of RYR1 bearing disease-associated mutations at the N-terminal region. When expressed in HEK293 cells, the mutant RYR1 caused abnormalities in Ca2+ homeostasis. MD simulations of WT and mutant RYR1s were performed using crystal structure of the N-terminal domain (NTD) monomer, consisting of A, B, and C domains. We found that the mutations located around the interdomain region differentially affected hydrogen bonds/salt bridges. Particularly, mutations at R402, which increase the open probability of the channel, cause clockwise rotation of BC domains with respect to the A domain by alteration of the interdomain interactions. Similar results were also obtained with artificial mutations that mimic alteration of the interactions. Our results reveal the importance of interdomain interactions within the NTD in the regulation of the RYR1 channel and provide insights into the mechanism of MH caused by the mutations at the NTD.

Development of the Dementia Assessment Sheet for Community-based Integrated Care System 8-items, a short version of the Dementia Assessment Sheet for Community-based Integrated Care System 21-items, for the assessment of cognitive and daily functions.

AIM: The present study aimed to: (i) examine the reliability and validity of the Dementia Assessment Sheet for Community-based Integrated Care System 21-items for classifying patients to the appropriate categories for glycemic targets in older patients; and (ii) develop a short version of the tool and examine its reliability and validity. METHODS: A total of 410 older individuals were recruited for this multicenter cross-sectional study. We classified them into three categories used for determining the glycemic target in older patients in Japan based on cognitive functions and activities of daily living. Exploratory factor analyses were used to select the eight items of the shorter version. The reliability and validity of the assessment tools were assessed using Cronbach's alpha coefficients and receiver operating characteristic analyses, respectively. RESULTS: The Dementia Assessment Sheet for Community-based Integrated Care System 21-items had three latent factors: cognitive function, instrumental activities of daily living and basic activities of daily living. The Dementia Assessment Sheet for Community-based Integrated Care System 8-items was developed based on each factor load quantity and was confirmed to have a strong correlation with the original version (r = 0.965, P < 0.001). Both tools significantly discriminated older adults belonging to category I from those belonging to category II or III, and category III from category I or II. CONCLUSIONS: Both tools had sufficient internal consistency and validity to classify older patients into the categories for determining the glycemic target in this population based on cognitive and daily functions. Geriatr Gerontol Int 2018; 18: 1458-1462.

Ray tracing analysis of overlapping objects in refraction contrast imaging.

We simulated refraction contrast imaging in overlapping objects using the ray tracing method. The easiest case, in which two columnar objects (blood vessels) with a density of 1.0 [g/cm3], run at right angles in air, was calculated. For absorption, we performed simulation using the Snell law adapted to the object's boundary. A pair of bright and dark spot results from the interference of refracted X-rays where the blood vessels crossed. This has the possibility of increasing the visibility of the image.

Estimation of contrast of refraction contrast imaging compared with absorption imaging-basic approach.

PURPOSE: We discuss the usefulness of the refraction contrast method using highly parallel X-rays as a new approach to minute lung cancer detection. The advantages of refraction contrast images are discussed in terms of contrast, and a comparison is made with absorption images. MATERIALS AND METHODS: We simulated refraction contrast imaging using globules with the density of water in air as models for minute lung cancer detection. The contrast intensified by bright and dark lines was compared on a globule with the contrast of absorption images. We adopted the Monte Carlo simulation to determine the strength of the profile curve of the photon counts at the detector. RESULTS: The obtained contrasts were more intense by two to three digits than those obtainable with the absorption contrast imaging method. CONCLUSION: The contrast in refraction contrast imaging was more intense than that obtainable with absorption contrast imaging. A two to three digit improvement in contrast means that it is possible to greatly reduce the exposure dose necessary for imaging. Therefore, it is expected to become possible to detect the interfaces of soft tissues, which are difficult to capture with conventional absorption imaging, at low dosages and high resolution.

[Geriatric medicine and long-term care insurance].

Long-term care insurance (LCI) started from April 2000 in Japan. LCI now occupies a central position in the health care of the aged. We reviewed all original papers and reports on LCI published in 1996-2002. At the end of 2002, we searched for papers on LCI in a computer database using the keyword of LCI, and found 3,606 papers. Authors and contents of each paper were categorized using 54 kinds of keywords. Frequent authors were government agencies, care managers, physical therapists, and physicians. When we analyzed these papers according to the places where LCI was used, more than 50% of reports concerned LCI at home. Most frequent keywords were Government/LCI system. Regional health, Physician' assessment and grades for care. Care management, Care manager, and Rehabilitation. Care manager was less observed after the start of LCI. In contrast, the use of keywords including Care service. Dementia, Geriatric syndrome, Nurse, Institutional medicine, Hospital care, Medicine for the aged, Terminal care, Dialysis therapy, Abuse of the aged, and Caregiver burden were increased after LCI. At the beginning of LCI, main concerns are on the new LCI system. However, more individual issues in the care of the aged are now discussed. New issues such as Abuse of the aged and Caregiver burden have been recently raised. From these observations, the role of geriatric medicine seems also to be changing after the induction of LCI. We would now contribute actively to crucial aspects of LCI, such as comprehensive assessment of the aged, functional medical network with care staffs, and new therapeutic approaches to each geriatric syndrome.

Water secretion associated with exocytosis in endocrine cells revealed by micro forcemetry and evanescent wave microscopy.

It has been a long belief that release of substances from the cell to the extracellular milieu by exocytosis is completed by diffusion of the substances from secretory vesicles through the fusion pore. Involvement of any mechanical force that may be superposed on the diffusion to enhance the releasing process has not been elucidated to date. We tackled this problem in cultured bovine chromaffin cells using direct and sensitive methods: the laser-trap forcemetry and the evanescent-wave fluorescence microscopy. With a laser beam, we trapped a micro bead in the vicinity of a cell (with 1 microm of separation) and observed movements of the bead optically. Electrical stimulation of the cell induced many of rapid and transient movements of the bead in a direction away from the cell surface. Upon the same stimulation, secretory vesicles stained with a fluorescent probe, acridine orange, and excited under the evanescent field illumination, showed a flash-like response: a transient increase in fluorescence intensity associated with a diffuse cloud of brightness, followed by a complete disappearance. These mechanical and fluorescence transients indicate a directional flow of substances. Blockers of the Cl(-) channel suppressed the rates of both responses in a characteristic way but not exocytotic fusion itself. Immunocytochemical studies revealed the presence of Cl(-) and K(+) channels on the vesicle membranes. These results suggest that the externalization of hormones or transmitters upon exocytosis of vesicles is augmented by secretion of water from the vesicle membrane through the widened fusion pore, possibly modulating the rate and reach of the hormone or transmitter release and facilitating transport of the signal molecules in intercellular spaces.