Vascular endothelial-cadherin as a marker of endothelial injury in preclinical Alzheimer disease.

OBJECTIVE: Endothelial dysfunction is an early and prevalent pathology in Alzheimer disease (AD). We here investigate the value of vascular endothelial-cadherin (VEC) as a cerebrospinal fluid (CSF) marker of endothelial injury in preclinical AD. METHODS: Cognitively normal participants (Clinical Dementia Rating [CDR] 0) from the Knight Washington University-ADRC were included in this study (n = 700). Preclinical Alzheimer's Cognitive Composite (PACC) scores, CSF VEC, tau, p-tau181, Aß42/Aß40, neurofilament light-chain (NFL) levels, and magnetic resonance imaging (MRI) assessments of white matter injury (WMI) were obtained from all participants. A subset of participants underwent brain amyloid imaging using positron emission tomography (amyloid-PET) (n = 534). Linear regression examined associations of CSF VEC with PACC and individual cognitive scores in preclinical AD. Mediation analyses examined whether CSF VEC mediated effects of CSF amyloid and tau markers on cognition in preclinical AD. RESULTS: CSF VEC levels significantly correlated with PACC and individual cognitive scores in participants with amyloid (A+T±N±; n = 558) or those with amyloid and tau pathologies (A+T+N±; n = 259), after adjusting for covariates. CSF VEC also correlated with CSF measures of amyloid, tau, and neurodegeneration and global amyloid burden on amyloid-PET scans in our cohort. Importantly, our findings suggest that CSF VEC mediates associations of CSF Aß42/Aß40, p-tau181, and global amyloid burden with cognitive outcomes in preclinical AD. INTERPRETATION: Our results support the utility of CSF VEC as a marker of endothelial injury in AD and highlight the importance of endothelial injury as an early pathology that contributes to cognitive impairment in even the earliest preclinical stages.

A randomized trial Examining The Impact Of Communicating Genetic And Lifestyle Risks For Obesity.

OBJECTIVE: Genetic testing for obesity is available directly to consumers, yet little is understood about its behavioral impact and its added value to nongenetic risk communication efforts based on lifestyle factors. METHODS: A randomized trial examined the short-term impact of providing personalized obesity risk information, using a 2 × 2 factorial design. Participants were recruited from the Coriell Personalized Medicine Collaborative (CPMC) and randomized to receive (1) no risk information (control), (2) genetic risk, (3) lifestyle risk, or (4) combined genetic/lifestyle risks. Baseline and 3-month follow-up survey data were collected. Analyses examined the impact of risk feedback on intentions to lose weight and self-reported weight. RESULTS: A total of 696 participants completed the study. A significant interaction effect was observed for genetic and lifestyle information on intent to lose weight (P = 0.0150). Those who received genetic risk alone had greater intentions at follow-up, compared with controls (P = 0.0034). The impact of receiving elevated risk information on intentions varied by source and combination of risks presented. Non-elevated genetic risk did not lower intentions. No group differences were observed for self-reported weight. CONCLUSIONS: Genetic risk information for obesity may add value to lifestyle risk information depending on the context in which it is presented.

Using the Coriell Personalized Medicine Collaborative Data to conduct a genome-wide association study of sleep duration.

Sleep is critical to health and functionality, and several studies have investigated the inherited component of insomnia and other sleep disorders using genome-wide association studies (GWAS). However, genome-wide studies focused on sleep duration are less common. Here, we used data from participants in the Coriell Personalized Medicine Collaborative (CPMC) (n = 4,401) to examine putative associations between self-reported sleep duration, demographic and lifestyle variables, and genome-wide single nucleotide polymorphism (SNP) data to better understand genetic contributions to variation in sleep duration. We employed stepwise ordered logistic regression to select our model and retained the following predictive variables: age, gender, weight, physical activity, physical activity at work, smoking status, alcohol consumption, ethnicity, and ancestry (as measured by principal components analysis) in our association testing. Several of our strongest candidate genes were previously identified in GWAS related to sleep duration (TSHZ2, ABCC9, FBXO15) and narcolepsy (NFATC2, SALL4). In addition, we have identified novel candidate genes for involvement in sleep duration including SORCS1 and ELOVL2. Our results demonstrate that the self-reported data collected through the CPMC are robust, and our genome-wide association analysis has identified novel candidate genes involved in sleep duration. More generally, this study contributes to a better understanding of the complexity of human sleep.

Common genetic risk for melanoma encourages preventive behavior change.

There is currently great interest in using genetic risk estimates for common disease in personalized healthcare. Here we assess melanoma risk-related preventive behavioral change in the context of the Coriell Personalized Medicine Collaborative (CPMC). As part of on-going reporting activities within the project, participants received a personalized risk assessment including information related to their own self-reported family history of melanoma and a genetic risk variant showing a moderate effect size (1.7, 3.0 respectively for heterozygous and homozygous individuals). Participants who opted to view their report were sent an optional outcome survey assessing risk perception and behavioral change in the months that followed. Participants that report family history risk, genetic risk, or both risk factors for melanoma were significantly more likely to increase skin cancer preventive behaviors when compared to participants with neither risk factor (ORs = 2.04, 2.79, 4.06 and p-values = 0.02, 2.86 × 10-5, 4.67 × 10-5, respectively), and we found the relationship between risk information and behavior to be partially mediated by anxiety. Genomic risk assessments appear to encourage positive behavioral change in a manner that is complementary to family history risk information and therefore may represent a useful addition to standard of care for melanoma prevention.

Image-guided resection of high-grade glioma: patient selection factors and outcome.

OBJECT: In patients with glioma, image-guided surgery helps to define the radiographic limits of the tumor to maximize safety and the extent of resection while minimizing damage to eloquent brain tissue. The authors hypothesize that image-guided resection (IGR) techniques are associated with improved outcomes in patients with malignant glioma. METHODS: Data recorded in 486 patients enrolled in the Glioma Outcomes Project were analyzed in this study. Demographic data and outcomes in patients who underwent IGR were compared with those in patients who underwent resection without IGR. Univariate analysis performed with chi-square testing was used to compare patient presentation, tumor characteristics, and death rates. Multivariate logistic regression was used to predict various outcome parameters. Patients who underwent IGR were younger and had smaller, lower-grade tumors than those in whom IGR was not performed. They were more likely to present with seizure and normal consciousness. Unexpectedly, gross-total resection was performed in significantly fewer patients with IGR than in individuals without IGR. Patients with IGR were more likely to be discharged home with the ability to live independently, and they had a shorter duration of hospital stay than patients without IGR. Survival was significantly longer in patients who underwent IGR, but multivariate analysis showed that glioblastoma multiforme (GBM) and age accounted for these observations. CONCLUSIONS: Selection bias occurs regarding patients who receive IGR; these biases include younger age, presentation with seizure and normal level of consciousness, tumor diameter less than 4 cm, and non-GBM on histopathological studies. Outcome appears to be improved in patients who undergo IGRs of high-grade gliomas. It is unclear if these improved outcomes are due to the selection of a more favorable patient population or to the IGR techniques themselves. It is likely that the full potential of image guidance in glioma surgery will not be realized until it is applied to a wider range of patients.