Lower Digit Symbol Substitution Score in the Oldest Old is Related to Magnetization Transfer and Diffusion Tensor Imaging of the White Matter

Background: Slowing information processing is common among community-dwelling elderly and it predicts greater mortality and disability risk. Slowing information processing is related to brain macro-structural abnormalities. Specifically, greater global atrophy and greater small vessel disease of the white matter (WM) have been associated with slower processing speed. However, community-dwelling elderly with such macro-structural abnormalities can maintain processing speed. The roles of brain micro-structure for slow processing in very old adults living in the community is uncertain, as epidemiological studies relating these brain markers to cognition and in the context of other health characteristics are sparse. Hypothesis: Information processing is cross-sectionally associated with WM micro-structure independent of overt macro-structural abnormalities and also independent of health related characteristics. Methods: Imaging indices of micro-structure diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI), macro-structure white matter hyperintensities (WMH), gray matter (GM) volume, digit symbol substitution test (DSST), and health characteristics were measured in 272 elderly (mean age 83 years old, 43% men, 40% black) living in the community. Results: The DTI- and MTI-indices of micro-structure from the normal appearing WM and not from the normal appearing GM were associated with DSST score independent of WMH and GM volumes. Associations were also independent of age, race, gender, mini-mental score, systolic blood pressure, and prevalent myocardial infarction. Interpretation: DTI and MTI-indices of normal appearing WM are indicators of information processing speed in this cohort of very old adults living in the community. Since processing slowing is a potent index of mortality and disability, these indices may serve as biomarkers in prevention or treatment trials of disability

A variant of sparse partial least squares for variable selection and data exploration

When data are sparse and/or predictors multicollinear, current implementation of sparse partial least squares (SPLS) does not give estimates for non-selected predictors nor provide a measure of inference. In response, an approach termed "all-possible" SPLS is proposed, which fits a SPLS model for all tuning parameter values across a set grid. Noted is the percentage of time a given predictor is chosen, as well as the average non-zero parameter estimate. Using a "large" number of multicollinear predictors, simulation confirmed variables not associated with the outcome were least likely to be chosen as sparsity increased across the grid of tuning parameters, while the opposite was true for those strongly associated. Lastly, variables with a weak association were chosen more often than those with no association, but less often than those with a strong relationship to the outcome. Similarly, predictors most strongly related to the outcome had the largest average parameter estimate magnitude, followed by those with a weak relationship, followed by those with no relationship. Across two independent studies regarding the relationship between volumetric MRI measures and a cognitive test score, this method confirmed a priori hypotheses about which brain regions would be selected most often and have the largest average parameter estimates. In conclusion, the percentage of time a predictor is chosen is a useful measure for ordering the strength of the relationship between the independent and dependent variables, serving as a form of inference. The average parameter estimates give further insight regarding the direction and strength of association. As a result, all-possible SPLS gives more information than the dichotomous output of traditional SPLS, making it useful when undertaking data exploration and hypothesis generation for a large number of potential predictors. © 2014 Olson Hunt, Weissfeld, Boudreau, Aizenstein, Newman, Simonsick, Van Domelen, Thomas, Yaffeand Rosano

COGNITIVE CORRELATES OF GAIT SPEED AMONG OLDER ADULTS FROM SIX COUNTRIES: FINDINGS FROM THE COSMIC COLLABORATION

Using data from population-based cohorts of older adults 65+ from six countries across three continents (N=6472), we aimed to (1) describe and (2) identify predictors of usual and rapid gait speed from studies participating in the Cohort Studies of Memory in an International Consortium (COSMIC) collaboration. We investigated whether clinical (BMI, hypertension, stroke, APOE status), psychological (cognition, mood, general health) and behavioral factors (smoking, drinking, physical activity) predicted gait speed similarly across cohorts; we used regression models controlling for demographics. Unadjusted usual gait speed ranged from 0.52-1.09 m/s and rapid gait speed ranged from 1.20-1.68 m/s. Lower BMI and better cognitive function consistently predicted faster usual and rapid gait speed in all cohorts. These patterns were not attenuated by demographics. Other psychological and behavioral factors were less consistently associated with gait. Taken together, gait speed is variable across ethnogeographic regions, but the influence of cognitive on gait is remarkably consistent

Investigating the impact of influenza on excess mortality in all ages in Italy during recent seasons (2013/14 - 2016/17 seasons)

Objectives: In recent years, Italy has been registering peaks in death rates, particularly among the elderly during the winter season. Influenza epidemics have been indicated as one of the potential determinants of such an excess. The objective of our study was to estimate the influenza-attributable contribution to excess mortality during the influenza seasons from 2013/14 to 2016/17 in Italy. Methods: We used the EuroMomo and the FluMomo methods to estimate the annual trend of influenza-attributable excess death rate by age group. Population data were provided by the National Institute of Statistics, data on influenza like illness and confirmed influenza cases were provided by the National Institutes of Health. As an indicator of weekly influenza activity (IA) we adopted the Goldstein index, which is the product of the percentage of patients seen with influenza-like illness (ILI) and percentage of influenza-positive specimens, in a given week. Results: We estimated excess deaths of 7,027, 20,259, 15,801 and 24,981 attributable to influenza epidemics in the 2013/14, 2014/15, 2015/16 and 2016/17, respectively, using the Goldstein index. The average annual mortality excess rate per 100,000 ranged from 11.6 to 41.2 with most of the influenza-associated deaths per year registered among the elderly. However children less than 5 years old also reported a relevant influenza attributable excess death rate in the 2014/15 and 2016/17 seasons (1.05/100,000 and 1.54/100,000 respectively). Conclusions: Over 68,000 deaths were attributable to influenza epidemics in the study period. The observed excess of deaths is not completely unexpected, given the high number of fragile very old subjects living in Italy. In conclusion, the unpredictability of the influenza virus continues to present a major challenge to health professionals and policy makers. Nonetheless, vaccination remains the most effective means for reducing the burden of influenza, and efforts to increase vaccine coverage and the introduction of new vaccine strategies (such as vaccinating healthy children) should be considered to reduce the influenza attributable excess mortality experienced in Italy and in Europe in the last seasons. Keywords: Flu, Mortality, Italy, Vaccinatio

Androgens and Adipose Tissue in Males: A Complex and Reciprocal Interplay

Clinical evidence shows that in males obesity is frequently associated with hypogonadism and vice versa; also, low testosterone levels have been considered a “hallmark” of metabolic syndrome in men. These observations indicate that there is a strict connection between anatomically and functionally distinct cell types such as white adipocytes and Leydig cells, that synthesize testosterone. Adipose tissue is able to control several functions of the testis through its products secreted in the bloodstream. On the other hand, circulating levels of testosterone and estradiol deeply affect adipocyte proliferation, differentiation, and fat mass distribution, hereby controlling critical metabolic functions, such as food intake, insulin sensitivity, vascular reactivity, and immunity. This paper highlights the existing clinical and experimental evidence linking androgens and adipose tissue and illustrates the consequences occurring when the balance between fat mass distribution and eugonadism is lost

The associations between serum brain-derived neurotrophic factor, potential confounders, and cognitive decline: A longitudinal study

Brain-derived neurotrophic factor (BDNF) plays a role in the maintenance and function of neurons. Although persons with Alzheimer's disease have lower cortical levels of BDNF, evidence regarding the association between circulating BDNF and cognitive function is conflicting. We sought to determine the correlates of BDNF level and whether BDNF level was prospectively associated with cognitive decline in healthy older adults. We measured serum BDNF near baseline in 912 individuals. Cognitive status was assessed repeatedly with the modified Mini-Mental Status Examination and the Digit Symbol Substitution test over the next 10 years. We evaluated the association between BDNF and cognitive decline with longitudinal models. We also assessed the association between BDNF level and demographics, comorbidities and health behaviors. We found an association between serum BDNF and several characteristics that are also associated with dementia (race and depression), suggesting that future studies should control for these potential confounders. We did not find evidence of a longitudinal association between serum BDNF and subsequent cognitive test trajectories in older adults, although we did identify a potential trend toward a cross-sectional association. Our results suggest that serum BDNF may have limited utility as a biomarker of prospective cognitive decline

Association of Dual Decline in Memory and Gait Speed With Risk for Dementia Among Adults Older Than 60 Years

Publisher's version (útgefin grein)Importance: Dual decline in both memory and gait speed may characterize a group of older individuals at high risk for future dementia. Objective: To assess the risk of dementia in older persons who experience parallel declines in memory and gait speed compared with those who experience no decline or decline in either memory or gait speed only. Design, Setting, and Participants: A multicohort meta-analysis was performed of 6 prospective cohort studies conducted between 1997 and 2018 in the United States and Europe. Participants were 60 years or older, had an initial gait speed of more than 0.6 m/s (ie, free of overt dismobility), with repeated measures of memory and gait speed before dementia diagnosis during a mean follow-up of 6.6 to 14.5 years. Within each study, participants were divided into 4 groups: memory decline only, gait speed decline only, dual decline, or no decline (hereafter referred to as usual agers). Gait decline was defined as a loss of 0.05 m/s or more per year; memory decline was defined as being in the cohort-specific lowest tertile of annualized change. Main Outcomes and Measures: Risk of incident dementia according to group membership was examined by Cox proportional hazards regression with usual agers as the reference, adjusted for baseline age, sex, race/ethnicity, educational level, study site, and baseline gait speed and memory. Results: Across the 6 studies of 8699 participants, mean age ranged between 70 and 74 years and mean gait speed ranged between 1.05 and 1.26 m/s. Incident dementia ranged from 5 to 21 per 1000 person-years. Compared with usual agers, participants with only memory decline had 2.2 to 4.6 times higher risk for developing dementia (pooled hazard ratio, 3.45 [95% CI, 2.45-4.86]). Those with only gait decline had 2.1 to 3.6 times higher risk (pooled hazard ratio, 2.24 [95% CI, 1.62-3.09]). Those with dual decline had 5.2 to 11.7 times the risk (pooled hazard ratio, 6.28 [95% CI, 4.56-8.64]). Conclusions and Relevance: In this study, dual decline of memory and gait speed was associated with increased risk of developing dementia among older individuals, which might be a potentially valuable group for preventive or therapeutic interventions. Why dual decline is associated with an elevated risk of dementia and whether these individuals progress to dementia through specific mechanisms should be investigated by future studies.This research work was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging (Drs Tian, Resnick, Launer, Simonsick, Studenski, and Ferrucci). The BLSA was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. The AGES-Reykjavik Study was funded by contract N01-AG-12100 from the National Institutes of Health; by the Intramural Research Program of the National Institute on Aging; and by the Icelandic Heart Association and the Icelandic Parliament. The Health ABC study was supported by National Institute on Aging contracts N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106; National Institute on Aging grant R01-AG028050; and National Institute of Nursing Research grant R01-NR012459, and was funded in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. The MCSA was supported by funding from the National Institutes of Health, National Institute on Aging (U01 AG006786), the Gerald and Henrietta Rauenhorst Foundation, and the Mayo Foundation for Medical Education and Research; and was made possible by the Rochester Epidemiology Project (R01 AG034676). The SNAC-K was supported by the funders of the Swedish National Study on Aging and Care; the Ministry of Health and Social Affairs, Sweden; the participating County Councils and Municipalities; and the Swedish Research Council. The InCHIANTI study was supported by National Institute on Aging contracts 263MD9164 (Dr Ferrucci) and 263 MD 821336, N01-AG-1-1, N01-AG-10211, and N01-AG-5-0002 (Dr Bandinelli), and partially supported by grant n PE 2011 02350413 of the Italian Ministry of Health (Dr Cherubini).Peer Reviewe

Sildenafil Reduces Insulin-Resistance in Human Endothelial Cells

The efficacy of Phosphodiesterase 5 (PDE5) inhibitors to re-establish endothelial function is reduced in diabetic patients. Recent evidences suggest that therapy with PDE5 inhibitors, i.e. sildenafil, may increase the expression of nitric oxide synthase (NOS) proteins in the heart and cardiomyocytes. In this study we analyzed the effect of sildenafil on endothelial cells in insulin resistance conditions in vitro

Fraisinib: a calixpyrrole derivative reducing A549 cell-derived NSCLC tumor in vivo acts as a ligand of the glycine-tRNA synthase, a new molecular target in oncology

Background and purpose: Lung cancer is the leading cause of death in both men and women, constituting a major public health problem worldwide. Non-small-cell lung cancer accounts for 85%–90% of all lung cancers. We propose a compound that successfully fights tumor growth in vivo by targeting the enzyme GARS1.Experimental approach: We present an in-depth investigation of the mechanism through which Fraisinib [meso-(p-acetamidophenyl)-calix(4)pyrrole] affects the human lung adenocarcinoma A549 cell line. In a xenografted model of non-small-cell lung cancer, Fraisinib was found to reduce tumor mass volume without affecting the vital parameters or body weight of mice. Through a computational approach, we uncovered that glycyl-tRNA synthetase is its molecular target. Differential proteomics analysis further confirmed that pathways regulated by Fraisinib are consistent with glycyl-tRNA synthetase inhibition.Key results: Fraisinib displays a strong anti-tumoral potential coupled with limited toxicity in mice. Glycyl-tRNA synthetase has been identified and validated as a protein target of this compound. By inhibiting GARS1, Fraisinib modulates different key biological processes involved in tumoral growth, aggressiveness, and invasiveness.Conclusion and implications: The overall results indicate that Fraisinib is a powerful inhibitor of non-small-cell lung cancer growth by exerting its action on the enzyme GARS1 while displaying marginal toxicity in animal models. Together with the proven ability of this compound to cross the blood–brain barrier, we can assess that Fraisinib can kill two birds with one stone: targeting the primary tumor and its metastases “in one shot.” Taken together, we suggest that inhibiting GARS1 expression and/or GARS1 enzymatic activity may be innovative molecular targets for cancer treatment