An atypical GABARAP binding module drives the pro-autophagic potential of the AML-associated NPM1c variant.

The nucleolar scaffold protein NPM1 is a multifunctional regulator of cellular homeostasis, genome integrity, and stress response. NPM1 mutations, known as NPM1c variants promoting its aberrant cytoplasmic localization, are the most frequent genetic alterations in acute myeloid leukemia (AML). A hallmark of AML cells is their dependency on elevated autophagic flux. Here, we show that NPM1 and NPM1c induce the autophagy-lysosome pathway by activating the master transcription factor TFEB, thereby coordinating the expression of lysosomal proteins and autophagy regulators. Importantly, both NPM1 and NPM1c bind to autophagy modifiers of the GABARAP subfamily through an atypical binding module preserved within its N terminus. The propensity of NPM1c to induce autophagy depends on this module, likely indicating that NPM1c exerts its pro-autophagic activity by direct engagement with GABARAPL1. Our data report a non-canonical binding mode of GABARAP family members that drives the pro-autophagic potential of NPM1c, potentially enabling therapeutic options.

Sino-European science and technology collaboration on personalized medicine: overview, trends and future perspectives.

Aim: Personalized medicine (PM) is revolutionizing biomedical and clinical research while improving the ways healthcare is delivered. The EU is at the forefront of science and innovation in this field, increasing collaborations worldwide. This paper aims to assess the status of recent collaborations between Europe and China in PM-related science, technology and funded research. Methods: We analyze scientific literature, patents and funding programs, respectively. Results: PM is a scientific and industrial priority in both geographical areas, but current levels of collaboration are suboptimal. To increase these levels, policy makers should promote cooperation between researchers, innovators, industries, regulators, funding agencies and healthcare systems, while providing a forum to exchange best practices, define common guidelines for PM implementation and promote public-private partnerships.

Incident Subjective Cognitive Decline Does Not Predict Mortality in the Elderly--Results from the Longitudinal German Study on Ageing, Cognition, and Dementia (AgeCoDe).

OBJECTIVE: Subjective cognitive decline (SCD) might represent the first symptomatic representation of Alzheimer's disease (AD), which is associated with increased mortality. Only few studies, however, have analyzed the association of SCD and mortality, and if so, based on prevalent cases. Thus, we investigated incident SCD in memory and mortality. METHODS: Data were derived from the German AgeCoDe study, a prospective longitudinal study on the epidemiology of mild cognitive impairment (MCI) and dementia in primary care patients over 75 years covering an observation period of 7.5 years. We used univariate and multivariate Cox regression analyses to examine the relationship of SCD and mortality. Further, we estimated survival times by the Kaplan Meier method and case-fatality rates with regard to SCD. RESULTS: Among 971 individuals without objective cognitive impairment, 233 (24.0%) incidentally expressed SCD at follow-up I. Incident SCD was not significantly associated with increased mortality in the univariate (HR = 1.0, 95% confidence interval = 0.8-1.3, p = .90) as well as in the multivariate analysis (HR = 0.9, 95% confidence interval = 0.7-1.2, p = .40). The same applied for SCD in relation to concerns. Mean survival time with SCD was 8.0 years (SD = 0.1) after onset. CONCLUSION: Incident SCD in memory in individuals with unimpaired cognitive performance does not predict mortality. The main reason might be that SCD does not ultimately lead into future cognitive decline in any case. However, as prevalence studies suggest, subjectively perceived decline in non-memory cognitive domains might be associated with increased mortality. Future studies may address mortality in such other cognitive domains of SCD in incident cases.

Gender differences in the effect of social support on health-related quality of life: results of a population-based prospective cohort study in old age in Germany.

PURPOSE: The causality between social predictors and HRQoL in old age remains almost unclear as only a few studies have examined the influence of social support on HRQoL in a longitudinal setting. Moreover, available studies investigating gender differences in the effect of social support on HRQoL in old age have been solely cross-sectional. Consequently, the aim of this study was to examine whether social support affects health-related quality of life (HRQoL) in old age and whether this effect is moderated by gender. METHODS: In a population-based cohort (N = 2443) of people aged 75 years and older in Germany, the development of HRQoL was prospectively observed over a 3-year period. Quality of life was quantified by using the visual analogue scale of the EQ-5D instrument. Social support was assessed by using the 14-item form of the questionnaire for social support (F-SozU K-14). In order to control for unobserved heterogeneity, fixed-effects regression analysis was used. RESULTS: In the total sample (ß = 0.55, p < 0.05) and in men (ß = 1.39, p < 0.001), a strong positive impact of social support on HRQoL was found. There was no significant effect of social support on HRQoL in women. The effect of social support on HRQoL was significantly moderated by gender (p < 0.05). CONCLUSIONS: Findings accentuate the fundamental role of social support in HRQoL in old age. Particularly in men, it is therefore crucial to strengthen the social ties in old age.

Longitudinal Predictors of Institutionalization in Old Age.

OBJECTIVE: To investigate time-dependent predictors of institutionalization in old age using a longitudinal approach. METHODS: In a representative survey of the German general population aged 75 years and older predictors of institutionalization were observed every 1.5 years over six waves. Conditional fixed-effects logistic regressions (with 201 individuals and 960 observations) were performed to estimate the effects of marital status, depression, dementia, and physical impairments (mobility, hearing and visual impairments) on the risk of admission to old-age home or nursing home. By exploiting the longitudinal data structure using panel econometric models, we were able to control for unobserved heterogeneity such as genetic predisposition and personality traits. RESULTS: The probability of institutionalization increased significantly with occurrence of widowhood, depression, dementia, as well as walking and hearing impairments. In particular, the occurrence of widowhood (OR = 78.3), dementia (OR = 154.1) and substantial mobility impairment (OR = 36.7) were strongly associated with institutionalization. CONCLUSION: Findings underline the strong influence of loss of spouse as well as dementia on institutionalization. This is relevant as the number of old people (a) living alone and (b) suffering from dementia is expected to increase rapidly in the next decades. Consequently, it is supposed that the demand for institutionalization among the elderly will increase considerably. Practitioners as well as policy makers should be aware of these upcoming challenges.

Determinants of health-related quality of life in older primary care patients: results of the longitudinal observational AgeCoDe Study.

BACKGROUND: In older patients with chronic diseases, focusing on subjective, patient-relevant outcomes, such as health-related quality of life (HRQoL), is more pertinent than pursuing clinical or laboratory target values. AIM: To investigate factors influencing the course of HRQoL in older (aged ≥78 years) primary care patients and to derive non-pharmacological recommendations for improving their quality of life. DESIGN AND SETTING: A population-based prospective longitudinal observational study featuring data analysis from waves 2 to 5 of the AgeCoDe study, which was conducted in six cities in Germany. METHOD: The HRQoL of 1968 patients over the course of 4.5 years was observed. Patients were, on average, aged 82.6 (±3.4) years and their HRQoL was measured using the EQ-5D visual analogue scale in a face-to-face assessment. Fixed-effects regression models were calculated to examine impact of change in potential influencing factors. This method allows unobserved heterogeneity to be controlled. RESULTS: The course of the participants' HRQoL declined with increasing age, walking and incident hearing impairment. Increasing the number of physical activities improved the HRQoL. These findings were modified by sex, education level, and depression. Especially in females and patients with rather low education levels, increased physical activity improved the subjects' HRQoL, while hearing impairment decreased it. Moving to an institution only improved the HRQoL in patients without depression or those with a low level of education (primary education). CONCLUSION: Motivating patients to increase their weekly physical activity and to focus on preserving their ability to walk are promising approaches to improving HRQoL in older age. Less-educated patients and those without depression can also benefit from moving into an institution (for example, a care or retirement home).

Prevalence and determinants of overweight and obesity in old age in Germany.

BACKGROUND: Mean body weight gradually increases with age. Yet, little data exists on the prevalence of excess weight in populations aged 80 years or older. Moreover, little is known about predictors of overweight and obesity in old age. Thus, the purpose of this study was: To present data on the prevalence of excess weight in old age in Germany, to investigate predictors of excess weight in a cross-sectional approach and to examine factors affecting excess weight in a longitudinal approach. METHODS: Subjects consisted of 1,882 individuals aged 79 years or older. The course of excess weight was observed over 3 years. Excess weight was defined as follows: Overweight (25 kg/m(2) ≤ BMI < 30 kg/m(2)) and obesity (BMI ≥ 30 kg/m(2)). We used fixed effects regressions to estimate effects of time dependent variables on BMI, and overweight or obesity, respectively. RESULTS: The majority was overweight (40.0%) or obese (13.7%). Cross-sectional regressions revealed that BMI was positively associated with younger age, severe walking impairments and negatively associated with cognitive impairments. Excess weight was positively associated with younger age, elementary education, walking impairments and physical inactivity, while excess weight was negatively associated with cognitive impairment. Longitudinal regressions showed that age and severely impaired walking disabilities reduced BMI. The probability of transitions to excess weight decreased considerably with older age and occurrence of severe walking impairments (overweight). CONCLUSIONS: Marked differences between predictors in cross- and longitudinal setting exist, underlining the complex nature of excess weight in old age.

Complex coevolution of depression and health-related quality of life in old age.

PURPOSE: To investigate the coevolution of depression and health-related quality of life (HRQoL) in old age. METHODS: In a representative survey of the German general population aged 75 years and older, the course of HRQoL and depression was observed over 4.5 years (3 waves). HRQoL was assessed by the Visual Analogue Scale (EQ VAS) of the EQ-5D instrument, while the Geriatric Depression Scale was used to measure depression. A panel vector autoregressive model was used to account for the complex coevolution of depression and HRQoL. Unobserved heterogeneity was taken into account by taking the first differences. RESULTS: We revealed a robust negative association between an initial change in HRQoL and a subsequent change in depression score, with substantial sex differences: In women there was a robust association, while in men the significance of this association depended on the model specification. Surprisingly, in the total sample and in both sexes, no robust association between an initial increase in depression and a subsequent change in HRQoL was found. CONCLUSION: Findings indicate that the direction of evolution from HRQoL to depression deserves more attention. Furthermore, treatment of depression in late life should aim at improving HRQoL in which remission of depressive symptoms is necessary but not sufficient.

Risk of dementia in elderly patients with the use of proton pump inhibitors.

Drugs that modify the risk of dementia in the elderly are of potential interest for dementia prevention. Proton pump inhibitors (PPIs) are widely used to reduce gastric acid production, but information on the risk of dementia is lacking. We assessed association between the use of PPIs and the risk of dementia in elderly people. Data were derived from a longitudinal, multicenter cohort study in elderly primary care patients, the German Study on Aging, Cognition and Dementia in Primary Care Patients (AgeCoDe), including 3,327 community-dwelling persons aged ≥ 75 years. From follow-up 1 to follow-up 4 (follow-up interval 18 months), we identified a total of 431 patients with incident any dementia, including 260 patients with Alzheimer's disease. We used time-dependent Cox regression to estimate hazard ratios of incident any dementia and Alzheimer's disease. Potential confounders included in the analysis comprised age, sex, education, the Apolipoprotein E4 (ApoE4) allele status, polypharmacy, and the comorbidities depression, diabetes, ischemic heart disease, and stroke. Patients receiving PPI medication had a significantly increased risk of any dementia [Hazard ratio (HR) 1.38, 95% confidence interval (CI) 1.04-1.83] and Alzheimer's disease (HR 1.44, 95% CI 1.01-2.06) compared with nonusers. Due to the major burden of dementia on public health and the lack of curative medication, this finding is of high interest to research on dementia and provides indication for dementia prevention.

Elevated HbA1c is associated with increased risk of incident dementia in primary care patients.

Type 2 diabetes mellitus (T2DM) is a risk factor of dementia. The effect of T2DM treatment quality on dementia risk, however, is unclear. 1,342 elderly individuals recruited via general practitioner registries (AgeCoDe cohort) were analyzed. This study analyzed the association between HbA1c level and the incidence of all-cause dementia (ACD) and of Alzheimer's disease dementia (referred to here as AD). HbA1c levels ≥6.5% were associated with 2.8-fold increased risk of incident ACD (p = 0.027) and for AD (p = 0.047). HbA1c levels ≥7% were associated with a five-fold increased risk of incident ACD (p = 0.001) and 4.7-fold increased risk of incident AD (p = 0.004). The T2DM diagnosis per se did not increase the risk of either ACD or AD. Higher levels of HbA1c are associated with increased risk of ACD and AD in an elderly population. T2DM diagnosis was not associated with increased risk if HbA1c levels were below 7%.

Cognitive performance before and after the onset of subjective cognitive decline in old age.

BACKGROUND: Our objectives were (1) to test the association between the report of subjective cognitive decline (SCD) and prospective objective cognitive performance in high age individuals and (2) to study the course of longitudinal cognitive performance before and after the first report of SCD. METHODS: Cognitively normal elderly participants of the German Study on Ageing, Cognition, and Dementia study (N = 2330) with SCD (subjective decline in memory with and without associated concerns) and without SCD at baseline were assessed over 8 years with regard to immediate and delayed verbal recall, verbal fluency, working memory, and global cognition. Baseline performance and cognitive trajectories were compared between groups. In addition, cognitive trajectories before and after the initial report of SCD (incident SCD) were modelled in those without SCD at baseline. RESULTS: Baseline performance in the SCD group was lower and declined more steeply in immediate and delayed verbal recall than in the control group (no SCD at baseline). This effect was more pronounced in the SCD group with concerns. Incident SCD was preceded by decline in immediate and delayed memory and word fluency. CONCLUSIONS: SCD predicts future memory decline. Incident SCD is related to previous cognitive decline. The latter finding supports the concept of SCD indicating first subtle decline in cognitive performance that characterizes preclinical Alzheimer's disease.

The role of spousal loss in the development of depressive symptoms in the elderly - implications for diagnostic systems.

BACKGROUND: In the revised version of the Diagnostic and Statistical Manual of Mental Disorders (DSM) the Mood Disorder Workgroup for DSM-V the bereavement exclusion criterion for the diagnosis of major depression has been eliminated. AIM: To investigate the impact of bereavement on the incidence of depression and depressive symptoms in the elderly. METHOD: Participants over 75 years from the longitudinal German Study on Ageing, Cognition, and Dementia in Primary Care Patients (AgeCoDe) that were still married at baseline were investigated (n=1,193). Data from four follow-ups (time frame: 6 years) were investigated. The response rate at baseline was 50.3%. Three clinical endpoints were analyzed: depressive symptoms according to Geriatric Depression Scale (1) GDS≥6, (2) GDS≥10, and (3) Major Depression (MD). The effect of loss was investigated using random-effects regression models. RESULTS: Experiencing a loss of spouse was predictive of a higher incidence in GDS≥6 (OR 4.52, 95% CI 2.6-7.9) and 10 (OR 5.59, 95% CI 1.8-17.0) even after adjusting for age, gender, impairment at baseline, and GDS score at baseline. Associations with MD were not significant (OR 1.77, 96% CI 0.9-3.5). CONCLUSIONS: Older adults experiencing the loss of their spouse are more likely to display elevated levels of depressive symptoms, that may reach a concerning level of severity.