Sedentary behavior, brain-derived neurotrophic factor and brain structure in midlife: A longitudinal brain MRI sub-study of the coronary artery risk development in young adults study.

BACKGROUND: Brain-derived neurotrophic factor levels are higher in those who are physically active and lower in people with cognitive dysfunction. This study investigated whether brain-derived neurotrophic factor mediated or modified the association of sedentary time to MRI-estimated brain volumes in midlife. METHODS: Baseline (n = 612) and five-year follow-up (n = 418) data were drawn from the multicenter Coronary Artery Risk Development in Young Adults Brain MRI sub-study, including Black and White participants (aged 50.3 years, 51.6% females, 38.6% Black). Sedentary time (hours per day) was categorized into quartiles with low ≤ 4.3 (reference) and high > 8.4. Outcomes of the study were total brain, white matter, gray matter, hippocampal volumes, and white matter fractional anisotropy at baseline and 5-year percent change from baseline. The study used general linear regression models to examine the mediation and moderation effects of brain-derived neurotrophic factor (natural log transformed) on the associations of sedentary time to brain outcomes. The authors adjusted the regression model for age, sex, race, intracranial volume, education, and vascular factors. RESULTS: Cross-sectionally, baseline participants with the highest sedentary time had a lower total brain (-12.2 cc; 95%CI: -20.7, -3.7), gray matter (-7.8 cc; 95%CI: -14.3, -1.3), and hippocampal volume (-0.2 cc; 95%CI: -0.3, 0.0) compared with populations with the lowest sedentary time. The brain-derived neurotrophic factor levels did not mediate the associations between brain measures and sedentary time. Brain-derived neurotrophic factor was found to moderate associations of sedentary time to total brain and white matter volume such that the brain volume difference between high and low sedentary time decreased as brain-derived neurotrophic factor levels increased. Longitudinally, higher baseline brain-derived neurotrophic factor level was associated with less brain volume decline. The longitudinal associations did not differ by sedentary time, and brain-derived neurotrophic factor did not mediate or moderate the association of sedentary time to brain measure changes. CONCLUSIONS: Higher brain-derived neurotrophic factor levels may buffer the negative effects of sedentary time on the brain

Isolation of quiescent and nonquiescent cells from yeast stationary-phase cultures

Quiescence is the most common and, arguably, most poorly understood cell cycle state. This is in part because pure populations of quiescent cells are typically difficult to isolate. We report the isolation and characterization of quiescent and nonquiescent cells from stationary-phase (SP) yeast cultures by density-gradient centrifugation. Quiescent cells are dense, unbudded daughter cells formed after glucose exhaustion. They synchronously reenter the mitotic cell cycle, suggesting that they are in a G0 state. Nonquiescent cells are less dense, heterogeneous, and composed of replicatively older, asynchronous cells that rapidly lose the ability to reproduce. Microscopic and flow cytometric analysis revealed that nonquiescent cells accumulate more reactive oxygen species than quiescent cells, and over 21 d, about half exhibit signs of apoptosis and necrosis. The ability to isolate both quiescent and nonquiescent yeast cells from SP cultures provides a novel, tractable experimental system for studies of quiescence, chronological and replicative aging, apoptosis, and the cell cycle

Identification of Circulating Proteins associated With General Cognitive Function among Middle-Aged and Older adults

Identifying circulating proteins associated with cognitive function may point to biomarkers and molecular process of cognitive impairment. Few studies have investigated the association between circulating proteins and cognitive function. We identify 246 protein measures quantified by the SomaScan assay as associated with cognitive function (p \u3c 4.9E-5, n up to 7289). Of these, 45 were replicated using SomaScan data, and three were replicated using Olink data at Bonferroni-corrected significance. Enrichment analysis linked the proteins associated with general cognitive function to cell signaling pathways and synapse architecture. Mendelian randomization analysis implicated higher levels of NECTIN2, a protein mediating viral entry into neuronal cells, with higher Alzheimer\u27s disease (AD) risk (p = 2.5E-26). Levels of 14 other protein measures were implicated as consequences of AD susceptibility (p \u3c 2.0E-4). Proteins implicated as causes or consequences of AD susceptibility may provide new insight into the potential relationship between immunity and AD susceptibility as well as potential therapeutic targets

52 Genetic Loci Influencing Myocardial Mass.

BACKGROUND: Myocardial mass is a key determinant of cardiac muscle function and hypertrophy. Myocardial depolarization leading to cardiac muscle contraction is reflected by the amplitude and duration of the QRS complex on the electrocardiogram (ECG). Abnormal QRS amplitude or duration reflect changes in myocardial mass and conduction, and are associated with increased risk of heart failure and death. OBJECTIVES: This meta-analysis sought to gain insights into the genetic determinants of myocardial mass. METHODS: We carried out a genome-wide association meta-analysis of 4 QRS traits in up to 73,518 individuals of European ancestry, followed by extensive biological and functional assessment. RESULTS: We identified 52 genomic loci, of which 32 are novel, that are reliably associated with 1 or more QRS phenotypes at p < 1 × 10(-8). These loci are enriched in regions of open chromatin, histone modifications, and transcription factor binding, suggesting that they represent regions of the genome that are actively transcribed in the human heart. Pathway analyses provided evidence that these loci play a role in cardiac hypertrophy. We further highlighted 67 candidate genes at the identified loci that are preferentially expressed in cardiac tissue and associated with cardiac abnormalities in Drosophila melanogaster and Mus musculus. We validated the regulatory function of a novel variant in the SCN5A/SCN10A locus in vitro and in vivo. CONCLUSIONS: Taken together, our findings provide new insights into genes and biological pathways controlling myocardial mass and may help identify novel therapeutic targets

Trends in the incidence of dementia: design and methods in the Alzheimer Cohorts Consortium.

Several studies have reported a decline in incidence of dementia which may have large implications for the projected burden of disease, and provide important guidance to preventive efforts. However, reports are conflicting or inconclusive with regard to the impact of gender and education with underlying causes of a presumed declining trend remaining largely unidentified. The Alzheimer Cohorts Consortium aggregates data from nine international population-based cohorts to determine changes in the incidence of dementia since 1990. We will employ Poisson regression models to calculate incidence rates in each cohort and Cox proportional hazard regression to compare 5-year cumulative hazards across study-specific epochs. Finally, we will meta-analyse changes per decade across cohorts, and repeat all analysis stratified by sex, education and APOE genotype. In all cohorts combined, there are data on almost 69,000 people at risk of dementia with the range of follow-up years between 2 and 27. The average age at baseline is similar across cohorts ranging between 72 and 77. Uniting a wide range of disease-specific and methodological expertise in research teams, the first analyses within the Alzheimer Cohorts Consortium are underway to tackle outstanding challenges in the assessment of time-trends in dementia occurrence

The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals

To dissect the genetic architecture of blood pressure and assess effects on target-organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure loci, of which 17 were novel and 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target-organ damage in multiple tissues, with minor effects in the kidney. Our findings expand current knowledge of blood pressure pathways and highlight tissues beyond the classic renal system in blood pressure regulation

Statistical methods in microarrays and high-throughput flow cytometry

Abstract-I Background: Heterogeneous cell populations have previously been described as noisy. However, recent studies have demonstrated that heterogeneity can be biologically significant. We present here an approach for rapid and complete identification of heterogeneous cell populations from high-throughput flow cytometry data. We have developed a novel measure Slope Differentiation Identification (SDI) using flow cytometry-based protein expression, quantifying the rate of change in protein expression between two conditions (exponential and stationary phase) of yeast cells, as a function of cell size or cell granularity. Results: SDI had superior Gene Ontology enrichment when compared with other approaches such as k-means clustering and an approach based on the bi-modality of the fluorescence intensity distribution. Cell populations were also validated using gradient-separation followed by microscopy, where proteins with high SDI measure showed significant levels of differentiation between high and low density cells. Conclusion: Overall, our approach has identified novel protein expression patterns that differentiate quiescent and non-quiescent cell populations. Abstract-II Background: With the advent of genomics, there has been a rapid increase in the use of two and onecolor microarrays, used to measure mRNA abundance for the entire genome. Variability in microarray analysis undermines its utility in identifying the entire subset of differentially expressed mRNAs. Recent microarray studies have shown that, although it is assumed that variances are constant for every hybridized spot within a microarray, variances may differ for each biological sample analyzed (Ritchie, Diyagama et al. 2006). Another common assumption is that log-intensity values for any given gene have a Normal distribution. For many datasets, both assumptions have been shown to be incorrect, resulting in distortions in the significance when testing for differential expression of each gene (Bar-Even, Paulsson et al. 2006; Wentzell, Karakach et al. 2006). Approach: To overcome the limitations of existing approaches in identifying significant, differentially expressed genes, we have developed a novel unsupervised statistical approach called Calibration Regression Analysis of Microarrays (CRAM) that uses a combination of empirical Bayes and regression calibration. The main novelty of our approach is the modeling of gene expression variances as a function of the log-intensity within each sample. Another version was later developed CRAM-GS in which the association between genes is captured using an adjusted gene correlation measure. Results: CRAM was compared to four existing approaches for identifying differentially expressed genes. Performance was based on the ability to identify co-regulated genes in the same Gene Ontology process. CRAM exhibited a marginal improvement in GO process enrichment compared with the other approaches. To the original datasets, three more were included in which the later version CRAM-GS, showed a significant improvement compared to CRAM, suggesting a major additional benefit of incorporating gene correlations into the model. All versions of CRAM were two orders of magnitude faster than the existing approaches. Overall, CRAM provides an adaptive, computationally efficient approach for accurate identification of differentially expressed genes.National Science Foundation (NSF) grant MCB-0645854 and National Institutes of Health (NIH) grant GM-67593 (to M.W.W) and NIH grant 1U54MH084690-01 (to L.S). P.H.T was supported by NIH/IMSD grant GM-060201. R.J was supported by NIH grant GM-075149.BiologyDoctoralUniversity of New Mexico. Biology Dept.Werner-Washburne, MaggieToolson, EricNatvig, DonaldWearing, Hele

Cardiac and Carotid Markers Link With Accelerated Brain Atrophy

OBJECTIVE: Pathologies in the heart-brain axis might, independently or in combination, accelerate the process of brain parenchymal loss. We aimed to investigate the association of serum N-terminal brain natriuretic peptide (NT-proBNP), as a marker of cardiac dysfunction, and carotid intima media thickness (CIMT), as a marker of carotid atherosclerosis burden, with structural brain changes. APPROACH AND RESULTS: In the longitudinal population-based AGES–Reykjavik Study, we included 2430 subjects (mean age 74.6, 41.4% male) with baseline data on NT-proBNP and CITM (assessed by Ultrasound imaging). Participants underwent a high-resolution brain MRI at baseline and five years later to assess total brain (TBV), grey matter (GMV) and white matter (WMV) volumes. Each unit higher log-transformed NT-proBNP was associated with 3.6 ml (95% CI: −6.0, −1.1) decline in TBV and 3.5 ml (95% CI: −5.7, −1.3) decline in GMV. Likewise, each millimeter higher CIMT was associated with 10.8 ml (95% CI: −17.3, −4.2) decline in TBV and 8.6 ml (95% CI: −14.4, −2.8) decline in GMV. There was no association between NT-proBNP and CIMT and changes in WMV. Compared to participants with low NT-proBNP and CIMT, participants with both high NT-proBNP and CIMT had 3.8 ml (95% CI: −6.0, −1.6) greater decline in their TBV and 4ml (95% CI: −6.0, −2.0) greater decline in GMW. These associations were independent of socio-demographic and cardiovascular factors. CONCLUSIONS: Older subjects with both cardiac dysfunction and carotid atherosclerosis are at an increased risk for brain parenchymal loss. Accumulated pathologies in the heart-brain axis might accelerate brain atrophy