Odor identification score as an alternative method for early identification of amyloidogenesis in Alzheimer's disease.

A simple screening test to identify the early stages of Alzheimer's disease (AD) is urgently needed. We investigated whether odor identification impairment can be used to differentiate between stages of the A/T/N classification (amyloid,  tau, neurodegeneration) in individuals with amnestic mild cognitive impairment or AD and in healthy controls. We collected data from 132 Japanese participants visiting the Toranomon Hospital dementia outpatient clinic. The odor identification scores correlated significantly with major neuropsychological scores, regardless of apolipoprotein E4 status, and with effective cerebrospinal fluid (CSF) biomarkers [amyloid ß 42 (Aß42) and the Aß42/40 and phosphorylated Tau (p-Tau)/Aß42 ratios] but not with ineffective biomarkers [Aß40 and the p-Tau/total Tau ratio]. A weak positive correlation was observed between the corrected odor identification score (adjusted for age, sex, ApoE4 and MMSE), CSF Aß42, and the Aß42/40 ratio. The odor identification score demonstrated excellent discriminative power for the amyloidogenesis stage , according to the A/T/N classification, but was unsuitable for differentiating between the p-Tau accumulation and the neurodegeneration stages. After twelve odor species were analyzed, a version of the score comprising only four odors-India ink, wood, curry, and sweaty socks-proved highly effective in identifying AD amyloidogenesis, showing promise for the screening of preclinical AD.

Higher Cholesterol Absorption Marker at Baseline Predicts Fewer Cardiovascular Events in Elderly Patients Receiving Hypercholesterolemia Treatment: The KEEP Study.

BACKGROUND: Higher cholesterol absorption has been reported to be related to a higher incidence of cardiovascular events (CVEs). The KEEP (Kyushu Elderly Ezetimibe Phytosterol) study, a substudy of the EWTOPIA 75 (Ezetimibe Lipid-Lowering Trial on Prevention of Atherosclerotic Cardiovascular Disease in 75 or Older) study, investigated the relationships of cholesterol absorption and synthesis markers with CVEs in older old individuals with hypercholesterolemia, particularly in relation to ezetimibe treatment. METHODS AND RESULTS: Eligible patients were those aged ≥75 years who had low-density lipoprotein cholesterol ≥140 mg/dL, no history of coronary artery disease, and no recent use of lipid-lowering drugs. Participants were randomly assigned into a diet-only or diet-plus-ezetimibe group. Baseline and 24-week follow-up blood samples were analyzed for cholesterol absorption (eg, campesterol) and synthesis markers (eg, lathosterol). Of 1287 patients, 1061 patients with baseline measurement were analyzed. Over a median follow-up of 4.0 years, 64 CVEs occurred. Higher campesterol levels at baseline were significantly associated with a lower risk of CVEs. After adjustment for sex, age, and treatment, the hazard ratios for the lowest to highest quartile categories of baseline campesterol were 1.00 (reference), 0.59 (95% CI, 0.30-1.17), 0.44 (95% CI, 0.21-0.94), and 0.44 (95% CI, 0.21-0.93), respectively (trend P=0.01). This association persisted after further adjustment for hypertension, diabetes, and other cardiovascular risk factors. Neither interactions with ezetimibe treatment nor mediating effects of the changes in cholesterol absorption markers were observed. CONCLUSIONS: The KEEP study indicated that higher campesterol levels without lipid-lowering drugs were associated with a lower incidence of CVEs in older old individuals with hypercholesterolemia who were subsequently treated with diet or ezetimibe. REGISTRATION: URL: https://www.umin.ac.jp; unique identifier: UMIN000017769.

Detection of intracranial aneurysms using deep learning-based CAD system: usefulness of the scores of CNN's final layer for distinguishing between aneurysm and infundibular dilatation.

PURPOSE: We evaluated the diagnostic performance of a clinically available deep learning-based computer-assisted diagnosis software for detecting unruptured aneurysms (UANs) using magnetic resonance angiography and assessed the functionality of the convolutional neural network (CNN) final layer score for distinguishing between UAN and infundibular dilatation (ID). MATERIALS AND METHODS: EIRL brain aneurysm (EIRL_BA) was used in this study. The subjects were 117 UAN and/or ID cases including 100 UAN lesions (average sizes of 2.56 ± 1.45 mm) and 40 ID lesions (average sizes of 1.75 ± 0.41 mm) in any of internal carotid artery, middle cerebral artery, and anterior communicating artery, and 123 normal controls. The sensitivity, specificity, and accuracy of EIRL_BA were determined for UAN and ID or UAN only. Furthermore, the relationship between the lesion category and score was examined using a linear regression analysis model, and the receiver operating characteristic (ROC) analysis was used to assess whether the scores represent UAN-like characteristics. RESULTS: EIRL_BA showed a total of 203 candidates (an average of 1.73/case) in UAN and/or ID cases and 98 candidates (an average of 0.80/case) in normal controls. For diagnosing either UAN/ID, EIRL_BA showed an overall sensitivity of 80%, specificity of 84.2%, and accuracy of 83.7%, resulting in the positive likelihood ratio of 5.0. For diagnosing UAN only, the overall sensitivity of 89.0, specificity of 82.6%, and accuracy of 83.2% resulting in the positive likelihood ratio of 5.1. In a linear regression analysis, the scores significantly increased in the candidates' first and second ranks in UAN (p < 0.05) but not in ID. An ROC analysis using the score for diagnosing UAN showed an area under the curve of 0.836. CONCLUSION: EIRL_BA is applicable for detecting small UAN, and the CNN's final layer scores may be an effective index for discriminating UAN and ID and representing the likelihood of UAN.

Toward the development of a vibrant, super-aged society: The future of medicine and society in Japan.

BACKGROUND: As Japan's population continues to age, it is estimated that the number of people aged ≥75 years will exceed 20 million by 2025. Furthermore, over the past 10 years, we have not reduced the difference between life expectancy and healthy life expectancy. Therefore, the extension of healthy life expectancy and the development of a healthy society are the most urgent issues. In terms of medical care, the changing times have inevitably led to changes in disease structures and medical demands; therefore, the medical delivery system has had to be changed to meet these demands. As dementia rapidly increases, it is important to address "frailty," a condition in which people become more vulnerable to environmental factors as they age, and there is a need to provide services to older people, particularly the old-old, that emphasize quality of life in addition to medical care. To realize a super-aged society that will remain vigorous and vibrant for many years, we need to rethink the future of Japanese medicine and healthcare, and the state of society. CURRENT SITUATION AND PROBLEMS: Disparity between healthy life expectancy and average life expectancy in the realization of a healthy society It is a challenge to build a society with a long and healthy life expectancy through comprehensive prevention and management of lifestyle-related diseases, as well as the elucidation of the factors that explain sex differences in healthy life expectancy, based on the recognition that lifestyle-related diseases in midlife are risk factors for frailty and dementia in old age. Challenges in medical care for building a super-aged and healthy society The challenges include promoting clinical guidelines suitable for older people, including lifestyle-related disease management, promoting comprehensive research on aging (basic research, clinical research and community collaboration research), and embodying a paradigm shift from "cure-seeking medical care" to "cure- and support-seeking medical care." Furthermore, the key to the future of integrated community care is the development of a comprehensive medical care system for older people in each region and the development of the next generation of medical personnel. Dissemination of frailty prevention measures in a super-aged society The concept of frailty encompasses the meaning of multifacetedness and reversibility; therefore, a comprehensive approach is required, including the renewal of conventional prevention activities in each region, such as the nutritional status of older people, physical activity including exercise, and various opportunities for social participation and participation conditions. Challenges of an unstable diet and undernutrition in older people According to the National Health and Nutrition Examination Survey of Japan, energy and protein intakes are low in Japanese people aged ≥75 years; particularly in people aged ≥80 years, low and insufficient intake of nutrients are prominent. Undernutrition in older people is increasing and is more pronounced in women. There are multiple factors behind this, including social factors, such as living alone, eating alone, poverty and other social factors, as well as problems with access to food security. Pharmacotherapy for older people: measures against polypharmacy In addition to the problems of adverse drug events, drug interactions, duplication of effects and the presence of drugs that "require particularly careful administration," it is also necessary to take measures against polypharmacy in older people, as well as medical economic issues, such as high drug costs and large amounts of remaining drugs. Barriers to this measure include multiple medical institution visits for each disease, lack of coordination between professions, and lack of understanding by patients and families. Role of local communities in a healthy society The decline in the working-age population is also a major challenge; however, we need to make a shift to use this declining birthrate and aging population as an opportunity rather than a crisis. As we look ahead to the coming of the 100-year age of life, we rethink the creation of a comprehensive society and community, and aim to create an age-free society where everyone can play an active role and live in peace, regardless of age. CONTENTS OF THE PROPOSAL: In this report, we have put together a vision for the future of an aging Japanese society from a broader perspective of how the environment and local communities should be, rather than simply from the perspective of individual health. We aim to convey this proposal to the Ministry of Health, Labor and Welfare, the Ministry of Education, Culture, Sports, Science and Technology, the Cabinet Office, and various professional organizations. The paradigm shift from "cure-seeking medical care" to "cure- and support-seeking medical care" should be promoted for the development of a healthy society While further promoting pre-emptive medical care in the medical care for older people, the development of multidisciplinary medical guidelines appropriate for older people should be promoted at the same time. In addition, we should promote basic aging research, clinical research (including the long-term care field) and transitional research that cover regional areas. Furthermore, while promoting the paradigm shift from "cure-seeking medical care" to "cure- and support-seeking medical care," the development of various comprehensive medical treatment systems for older people and the strengthening of integrated community care systems should be promoted. Development of the next generation of medical personnel to comprehensively deal with geriatric care, including training geriatric specialists, should be promoted As the number of older people with multimorbidities and frailty rapidly increases in the future, we should promote the development of the next generation of medical personnel who can comprehensively handle medical care for older people, including training leading geriatricians in cooperation with multiple professions in the integrated community care system to provide sufficient medical care. Countermeasures for frailty in older people should be promoted from medical and community planning perspectives To address frailty, which requires comprehensive evaluation and intervention, the three pillars of frailty prevention (nutrition, exercise and social participation) should be incorporated and addressed as part of community development within each municipality, taking into account local characteristics. In particular, it is necessary to revise the way of thinking about nutrition management in older people and the guidelines of the societies in the field. In addition, it is important to strengthen industry-academia-government-private partnerships in each region, taking into account not only medical issues, but also social factors, and encourage the development of momentum in the entire region regarding measures against undernutrition in older people. Polypharmacy measures should be promoted in pharmacotherapy for older people It is necessary to promote cooperation between physicians and pharmacists, establish other multiprofessional cooperation systems, and develop medical and long-term care insurance systems to support this. It is also essential to change the public's mindset, and awareness-raising activities at all levels are required, including the enhancement of educational materials for medical caregivers and the general public. In addition, the economic impact of healthcare using big data should be timely clarified. Innovation in medical and urban planning perspectives should be promoted In the future, it will be necessary to modify and update multidisciplinary approaches such as social participation (e.g. participation in a salon) with a view to innovation in both medical care and community development, especially on the idea of a symbiotic community. In addition, industry-academia-government-private partnership is necessary, including all aforementioned, such as places where people can play an active role in the rest of their lives (such as employment), promotion of human connections, promotion of technology to support older people and support for daily life. Geriatr Gerontol Int 2021; 21: 601-613.

Association between low muscle mass and metabolic syndrome in elderly Japanese women.

Metabolic syndrome (MetS) is an important predictor of mortality in older adulthood, but it is not reliably related to measures of body composition such as body mass index in older adults, as opposed to those in earlier life stages. Previous research suggests that skeletal muscle mass is related to cardiovascular risk in older adulthood, but it is difficult to measure muscle mass accurately and independently of body fat. This study aimed to examine the relationship between body composition and cardiovascular risk factors among women in older adulthood. A cross-sectional observational clinical study was conducted at a single medical clinic in Tokyo, Japan. Participants included 90 healthy Japanese women aged 65 years and older. MetS risk factors were assessed. Appendicular skeletal muscle mass (ASM) was assessed using dual-emission X-ray absorptiometry. Visceral fat area (VFA) was measured using computed tomography. VFA positively correlated with ASM and MetS, whereas ASM and MetS did not correlate with each other. Using VFA and ASM data in a MetS multiple linear regression model, the association between VFA and MetS remained positive, whereas a significant negative relationship emerged between ASM and MetS. Lower muscle mass was independently associated with higher cardiovascular risk after controlling for VFA. Clinical interventions to reduce muscle loss in older adulthood may be beneficial for reducing the risk of MetS and improving cardiovascular health.

Ezetimibe Lipid-Lowering Trial on Prevention of Atherosclerotic Cardiovascular Disease in 75 or Older (EWTOPIA 75): A Randomized, Controlled Trial.

BACKGROUND: Evidence regarding the primary prevention of coronary artery disease events by low-density lipoprotein cholesterol (LDL-C) lowering therapy in older individuals, aged ≥75 years, is insufficient. This trial tested whether LDL-C-lowering therapy with ezetimibe is useful for the primary prevention of cardiovascular events in older patients. METHODS: This multicenter, prospective, randomized, open-label, blinded end-point evaluation conducted at 363 medical institutions in Japan examined the preventive efficacy of ezetimibe for patients aged ≥75 years, with elevated LDL-C without history of coronary artery disease. Patients, who all received dietary counseling, were randomly assigned (1:1) to receive ezetimibe (10 mg once daily) versus usual care with randomization stratified by site, age, sex, and baseline LDL-C. The primary outcome was a composite of sudden cardiac death, myocardial infarction, coronary revascularization, or stroke. RESULTS: Overall, 3796 patients were enrolled between May 2009 and December 2014, and 1898 each were randomly assigned to ezetimibe versus control. Median follow-up was 4.1 years. After exclusion of 182 ezetimibe patients and 203 control patients because of lack of appropriate informed consent and other protocol violations, 1716 (90.4%) and 1695 (89.3%) patients were included in the primary analysis, respectively. Ezetimibe reduced the incidence of the primary outcome (hazard ratio [HR], 0.66; 95% CI, 0.50-0.86; P=0.002). Regarding the secondary outcomes, the incidences of composite cardiac events (HR, 0.60; 95% CI, 0.37-0.98; P=0.039) and coronary revascularization (HR, 0.38; 95% CI, 0.18-0.79; P=0.007) were lower in the ezetimibe group than in the control group; however, there was no difference in the incidence of stroke, all-cause mortality, or adverse events between trial groups. CONCLUSIONS: LDL-C-lowering therapy with ezetimibe prevented cardiovascular events, suggesting the importance of LDL-C lowering for primary prevention in individuals aged ≥75 years with elevated LDL-C. Given the open-label nature of the trial, its premature termination and issues with follow-up, the magnitude of benefit observed should be interpreted with caution. Clinical Registration: URL: https://www.umin.ac.jp. Unique identifier: UMIN000001988.

Trends in Polypharmacy in Japan: A Nationwide Retrospective Study.

OBJECTIVES: To describe and examine trends in polypharmacy according to age in Japan from 2010 to 2016. DESIGN: Retrospective observational study. SETTING: Outpatient settings. PARTICIPANTS: Japanese individuals aged 20 and older. MEASUREMENTS: We analyzed pharmacy claims data that the Japanese Ministry of Health, Labor, and Welfare provided in the Survey of Medical Care Activities in Public Health Insurance from 2010 to 2016. The use of 5 or more oral prescription medications per month was defined as polypharmacy and of 10 or more as excessive polypharmacy. Regression analysis was used to estimate trends in polypharmacy with annual percentage changes. Using number of medications (polypharmacy vs excessive polypharmacy), trends in polypharmacy and crude and age-adjusted rates of polypharmacy per 1,000 persons were calculated according to year and age group (20-34, 35-49, 50-64, 65-79, ≥ 80). RESULTS: We analyzed 240 million pharmacy claims data. The age-adjusted monthly prevalence rate of polypharmacy increased from 85.2 to 93.8 per 1,000 persons per month and of excessive polypharmacy from 13.6 to 14.0 per 1,000 persons per month from 2010 to 2016 in the entire study population. The highest rate of polypharmacy (per 1,000 persons) was observed in 2016 in those aged 80 and older (326.8), followed by those aged 65 to 79 (167.3). The polypharmacy rate increased by 6.3% (95% confidence interval (CI)=4.0-8.7) per year from 2010 to 2012, then decreased by 0.7% (95% CI=-1.3-0.0) per year from 2012 to 2016. The rate of excessive polypharmacy increased by 4.5% (95% CI=1.1-8.0) per year from 2010 to 2013 and then decreased by 3.7% (95% CI=-6.7 to -0.6) per year from 2013 to 2016. CONCLUSION: The overall trend of polypharmacy in Japan increased during the study period, although the increase ceased in 2013 and then declined from 2013 to 2016. Policy changes in Japan might be responsible for some of the changes. J Am Geriatr Soc 66:2267-2273, 2018.

Role of autonomic nervous activity, as measured by heart rate variability, on the effect of mortality in disabled older adults with low blood pressure in long-term care.

AIM: Previous studies have shown the relationship between low blood pressure and high mortality in frail, disabled older adults in long-term care. However, the mechanism of this relationship is still unclear. We hypothesized that autonomic nervous activity decline is involved in the relationship between low blood pressure and high mortality. METHODS: The present prospective cohort study recruited 61 participants aged ≥75 years. The data from 24-h Holter monitoring and blood pressure recorded by ambulatory blood pressure monitoring were collected. Measured data were divided into three categories: 24-h, daytime and night-time. From power spectral density in the electrocardiogram, low frequency, high frequency and low frequency/high frequency ratio were calculated. The primary end-point was death. RESULTS: High blood pressure was connected to both high daytime low frequency and high frequency (partial correlation coefficients: 0.42, P < 0.05 and 0.35, P < 0.05, respectively). In addition, the low blood pressure group had higher mortality than the high blood pressure group, and disabled older adults in long-term care and those with elevated daytime systolic and diastolic blood pressure had less risk of mortality compared with those without (systolic: hazard ratio 0.89, 95% confidence interval 0.83-0.96, P = 0.003; diastolic: hazard ratio 0.98, 95% confidence interval 0.79-1.00, P = 0.049). The average blood pressures in the high blood pressure groups were approximately 140/80 mmHg and were connected to low mortality. CONCLUSIONS: Attenuated autonomic nervous activity might lead to low blood pressure in the daytime and high mortality in disabled older adults in long-term care. Geriatr Gerontol Int 2018; 18: 1153-1158.

Inhibition of interleukin-6 decreases atrogene expression and ameliorates tail suspension-induced skeletal muscle atrophy.

BACKGROUND: Interleukin-6 (IL-6) is an inflammatory cytokine. Whether systemic IL-6 affects atrogene expression and disuse-induced skeletal muscle atrophy is unclear. METHODS: Tail-suspended mice were used as a disuse-induced muscle atrophy model. We administered anti-mouse IL-6 receptor antibody, beta-hydroxy-beta-methylbutyrate (HMB) and vitamin D to the mice and examined the effects on atrogene expression and muscle atrophy. RESULTS: Serum IL-6 levels were elevated in the mice. Inhibition of IL-6 receptor suppressed muscle RING finger 1 (MuRF1) expression and prevented muscle atrophy. HMB and vitamin D inhibited the serum IL-6 surge, downregulated the expression of MuRF1 and atrogin-1 in the soleus muscle, and ameliorated atrophy in the mice. CONCLUSION: Systemic IL-6 affects MuRF1 expression and disuse-induced muscle atrophy.

Loss of kallikrein-related peptidase 7 exacerbates amyloid pathology in Alzheimer's disease model mice.

Deposition of amyloid-ß (Aß) as senile plaques is one of the pathological hallmarks in the brains of Alzheimer's disease (AD) patients. In addition, glial activation has been found in AD brains, although the precise pathological role of astrocytes remains unclear. Here, we identified kallikrein-related peptidase 7 (KLK7) as an astrocyte-derived Aß degrading enzyme. Expression of KLK7 mRNA was significantly decreased in the brains of AD patients. Ablation of Klk7 exacerbated the thioflavin S-positive Aß pathology in AD model mice. The expression of Klk7 was upregulated by Aß treatment in the primary astrocyte, suggesting that Klk7 is homeostatically modulated by Aß-induced responses. Finally, we found that the Food and Drug Administration-approved anti-dementia drug memantine can increase the expression of Klk7 and Aß degradation activity specifically in the astrocytes. These data suggest that KLK7 is an important enzyme in the degradation and clearance of deposited Aß species by astrocytes involved in the pathogenesis of AD.

In Vitro and In Vivo Anticancer Activity of Human ß-Defensin-3 and Its Mouse Homolog.

BACKGROUND/AIM: Defensins comprise a family of mammalian cationic antimicrobial peptides. We investigated the anticancer effects of human ß-defensin-3 (hBD3) and its mouse homolog, Defb14, on lung cancer cells. MATERIALS AND METHODS: We stained lung cancer cells cultured after treatment with the defensin peptide using propidium iodide and Hoechst 33342. In vivo, Defb14 peptide or vehicle was continuously infused near subcutaneous Lewis lung carcinoma cell tumor in mice. After 9-day infusion, the weights of excised tumors were determined. RESULTS: A 10-min treatment with hBD3 (70 µg/ml) induced propidium iodide uptake in lung cancer cells. The anticancer activity of hBD3 was significantly more potent than the activity of other defensin isoforms. Continuous infusion of Defb14 peptide showed significant tumor-growth suppression in Lewis lung carcinoma cells in mice. CONCLUSION: Our study demonstrated the suppression of tumor growth by Defb14 peptide in an animal model.

Rigid Cooperation of Per1 and Per2 proteins.

Period circadian clock (Per) genes Per1 and Per2 have essential roles in circadian oscillation. In this study, we identified a new role of Per1-Per2 cooperation, and its mechanism, using our new experimental methods. Under constant light conditions, the period length of Per1 and Per2 knockout mice depended on the copy number ratio of Per1:Per2. We then established a light-emitting diode-based lighting system that can generate any pattern of light intensity. Under gradually changing light in the absence of phase shift with different periods, both Per1((-/-)) and Per2((-/-)) mice were entrained to a broader range of period length than wild-type mice. To analyse Per1-Per2 cooperative roles at the cell culture level, we established a Per2 knockout-rescue system, which can detect period shortening in a familial advanced sleep phase syndrome (FASPS) mutant. Upon introduction of the Per1 coding region in this system, we saw period shortening. In conclusion, short period-associated protein Per1 and long period-associated Per2 cooperated to rigidly confine the circadian period to "circa" 24-h. These results suggest that the rigid circadian rhythm maintained through the cooperation of Per1-Per2 could negatively impact modern society, in which the use of artificial lighting is ubiquitous, and result in circadian disorders, including delirium.

A novel organ culture model of aorta for vascular calcification.

Vascular calcification is a characteristic feature of aging, atherosclerosis, diabetes mellitus, and end-stage renal disease. The use of organ culture provides complementary information that may bridge the gap between traditional cell culture and animal models, and establishes easily controlled experimental conditions. Therefore, we investigated whether organ culture of the aorta could be used as a model of vascular calcification, applying it to animal models of other conditions. Thoracic aortas were dissected from C57BL/6 mice and cultured. To induce vascular calcification, stimulation with inorganic phosphate (Pi) was performed. Morphometric assessment of medial calcium deposition was quantitatively performed, and the amount of dissolved calcium was measured. Pi-stimulation induced calcium deposition in medial layers in a time- and dose-dependent manner. To investigate the phenotypic change of vascular smooth muscle cells (VSMC), the expression of Runx2, osterix, osteocalcin, and ALP activity were determined. Finally, to investigate the influence of Pi-stimulation on the cultured aorta in other models, aortas from streptozotocin (STZ)-induced diabetic mice, aged mice, and Sirt1 knockout (+/-) mice were dissected. These cultures showed a greater tendency for aortic calcification by Pi-stimulation than did control cultures. These results indicate that organ culture of the aorta from mice reflects the state of calcification and suggests that this model will be useful to explore the molecular mechanisms of vascular calcification and the pathology of senescence.

Interview- and questionnaire-based surveys on elderly patients' wishes about artificial nutrition and hydration during end-of-life care.

AIM: To promote advance directives, it is crucial to understand how many older persons have wishes related to end-of-life care. Additionally, it is important to understand how cognitive function or mood affect these wishes. METHODS: For the interview-based survey, 99 inpatients aged 75 years or older were enrolled after excluding patients with a Mini-Mental State Examination score of 20 or less. For the questionnaire-based survey, 99 outpatients aged 75 years or older without dementia were enrolled. Both surveys comprised the same items on older patients' wishes related to artificial nutrition and hydration (ANH) during end-of-life care. RESULTS: Of the total enrolled patients, 76.8% participated in the interviews. Of these, 50.0% were against ANH during their end-of-life care, including the patients who were definitely against ANH (26.3%). In contrast, just 5.3% wished to receive ANH. In the questionnaire survey, 65.6% of the respondents were against ANH, and 4.9% wished to receive ANH. Aging and Mini-Mental State Examination scores of less than 24 were significantly associated with a higher tendency to decline from participating in the interview. However, the distribution of the interview answers was not associated with age, Mini-Mental State Examination or Geriatric Depression Scale scores. Of the interviewed patients, 84.2% agreed to their responses being preserved in their medical records. CONCLUSIONS: Although the majority of the elderly patients were against ANH during end-of-life care, many patients did not have definite wishes in Japan. The percentage of those who were against ANH was not associated with cognitive function or depressive state. Geriatr Gerontol Int 2016; 16: 1204-1210.

Protective effects of NMDA receptor antagonist, memantine, against senescence of PC12 cells: A possible role of nNOS and combined effects with donepezil.

Alzheimer disease (AD) is a neurodegenerative disorder characterized by cognitive dysfunction. The pathology of AD is mainly related to amyloid ß (Aß)-peptides, but glutamate-mediated toxicity is also one of the main processes of memory impairment in AD. Glutamate is the main excitatory neurotransmitter in the central nervous system (CNS) and is particularly involved in synaptic plasticity, memory, and learning. Memantine is a low-affinity voltage-dependent noncompetitive antagonist at glutamatergic NMDA receptors. Here,we investigated whether memantine protects against glutamate-induced senescence. In PC12 cells, treatment with glutamate induced senescent phenotypes as judged by the cell appearance and senescence-associated ß-galactosidase (SA-ßgal) in parallel with decreased SIRT1 and increased p53 expression. However, treatment with memantine decreased glutamate-induced senescent PC12 cells and reversed the changes in SIRT1 and p53 expression. Glutamate is known to stimulate the production of NO and O2(-) and has the capacity to generate ONOO(-) in the CNS. Therefore, we investigated whether glutamate activates nNOS and memantine reverses it. Treatment with glutamate increased nNOS expression, activity, and production of NO,whereas memantine blocked them. Next, the in vivo effects of memantine on cognitive function in senescence-accelerated mouse prone 8 (SAMP8), as a model of AD, were investigated. In the Morris water maze test, SAMP8 showed a marked decline in performance, but memantine administration improved it. Moreover, neuronal senescence and the level of oxidative stress in the hippocampus were decreased by memantine. Finally, the effects of combination treatment with memantine and donepezil, a cholinesterase inhibitor, were investigated. We observed additive effects of memantine and donepezil on the senescent phenotype of PC12 cells and the hippocampus of SAMP8. These results indicate that inhibition of the NMDA receptor by memantine leads to a decrease innNOS activity and results in a reduction of glutamate-induced senescence. Thus, our present study suggests a critical role of memantine in the prevention of neuronal aging, and supports that donepezil has a combined effect with memantine.

Suppressive Role of PPARγ-Regulated Endothelial Nitric Oxide Synthase in Adipocyte Lipolysis.

INTRODUCTION: Metabolic syndrome causes insulin resistance and is associated with risk factor clustering, thereby increasing the risk of atherosclerosis. Recently, endothelial nitric oxide synthase deficient (eNOS-/-) mice have been reported to show metabolic disorders. Interestingly, eNOS has also been reported to be expressed in non-endothelial cells including adipocytes, but the functions of eNOS in adipocytes remain unclear. METHODS AND RESULTS: The eNOS expression was induced with adipocyte differentiation and inhibition of eNOS/NO enhanced lipolysis in vitro and in vivo. Furthermore, the administration of a high fat diet (HFD) was able to induce non-alcoholic steatohepatitis (NASH) in eNOS-/- mice but not in wild type mice. A PPARγ antagonist increased eNOS expression in adipocytes and suppressed HFD-induced fatty liver changes. CONCLUSIONS: eNOS-/- mice induce NASH development, and these findings provide new insights into the therapeutic approach for fatty liver disease and related disorders.