Meta-analysis of 8q24 for seven cancers reveals a locus between NOV and ENPP2 associated with cancer development.

BACKGROUND: Human chromosomal region 8q24 contains several genes which could be functionally related to cancer, including the proto-oncogene c-MYC. However, the abundance of associations around 128 Mb on chromosome 8 could mask the appearance of a weaker, but important, association elsewhere on 8q24. METHODS: In this study, we completed a meta-analysis of results from nine genome-wide association studies for seven types of solid-tumor cancers (breast, prostate, pancreatic, lung, ovarian, colon, and glioma) to identify additional associations that were not apparent in any individual study. RESULTS: Fifteen SNPs in the 8q24 region had meta-analysis p-values < 1E-04. In particular, the region consisting of 120,576,000-120,627,000 bp contained 7 SNPs with p-values < 1.0E-4, including rs6993464 (p = 1.25E-07). This association lies in the region between two genes, NOV and ENPP2, which have been shown to play a role in tumor development and motility. An additional region consisting of 5 markers from 128,478,000 bp - 128,524,000 (around gene POU5F1B) had p-values < 1E-04, including rs6983267, which had the smallest p-value (p = 6.34E-08). This result replicates previous reports of association between rs6983267 and prostate and colon cancer. CONCLUSIONS: Further research in this area is warranted as these results demonstrate that the chromosomal region 8q24 may contain a locus that influences general cancer susceptibility between 120,576 and 120,630 kb.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Mortality in mild cognitive impairment varies by subtype, sex, and lifestyle factors: The mayo clinic study of aging

© 2015 - IOS Press and the authors. All rights reserved. Background: Etiologic differences in mild cognitive impairment (MCI) subtypes may impact mortality. Objective: To assess the rate of death in MCI overall, and by subtype, in the population-based Mayo Clinic Study of Aging. Methods: Participants aged 70-89 years at enrollment were clinically evaluated at baseline and 15-month intervals to assess diagnoses of MCI and dementia. Mortality in MCI cases versus cognitively normal (CN) individuals was estimated using Cox proportional hazards models. Results: Over a median follow-up of 5.8 years, 331 of 862 (38.4%) MCI cases and 224 of 1,292 (17.3%) cognitively normal participants died. Compared to CN individuals, mortality was elevated in persons with MCI (hazard ratio [HR] = 1.79; 95% CI: 1.41 to 2.27), and was higher for non-amnestic MCI (naMCI; HR = 2.40; 95% CI: 1.72 to 3.36) than for amnestic MCI (aMCI; HR = 1.61; 95% CI: 1.25 to 2.09) after adjusting for confounders. Mortality varied significantly by sex, education, history of heart disease, and engaging in moderate physical exercise (p for interaction \u3c0.05 for all). Mortality rate estimates were highest in MCI cases who were men, did not exercise, had heart disease, and had higher education versus CN without these factors, and for naMCI cases versus aMCI cases without these factors. Conclusions: These findings suggest stronger impact of etiologic factors on naMCI mortality. Prevention of heart disease, exercise vigilance, may reduce MCI mortality and delayed MCI diagnosis in persons with higher education impacts mortality

Association of pancreatic polypeptide with mild cognitive impairment varies by APOE ε4 allele

© 2015 Roberts, Aakre, Cha, Kremers, Mielke, Velgos, Geda, Knopman and Petersen. We conducted a preliminary case-control investigation of the association of pancreatic polypeptide (PP) with mild cognitive impairment (MCI) in 202 MCI cases (mean age, 81.6 years) and 202 age- and sex-matched cognitively normal controls in the Mayo Clinic Study of Aging. Plasma PP was measured and examined as the natural logarithm (continuous) and dichotomized at the median. The OR (95% CI) of MCI increased with increasing PP [1.46 (1.04-2.05)]. There was a negative interaction of PP with apolipoprotein E (APOE) ε4 allele; compared to the reference group (no APOE ε4 allele and low PP), the OR (95% CI) for combinations of ε4 and PP were: 2.64 (1.39-5.04) for APOE ε4 plus low PP; 2.09 (1.27-3.45) for no APOE ε4 plus high PP; and 1.91 (1.04-3.53) for no APOE ε4 plus high PP (P for interaction = 0.017). There was also a trend toward a negative interaction with type 2 diabetes (P for interaction = 0.058). Compared to no diabetes and low PP, the OR (95% CI) was 3.02 (1.22-7.46) for low PP plus diabetes but 1.80 (1.01-3.22) for high PP plus diabetes. Participants with high PP had a greater mean (SD) weight loss (kilograms per decade) than persons with low PP [-2.27 (4.07) vs. -1.61 (5.24); P = 0.016]. MCI cases had a non-significantly greater weight loss per decade compared to controls. These findings suggest that high PP alone or jointly with APOE ε4 allele or type 2 diabetes is associated with MCI, and that high PP may mitigate some effects of APOE ε4 allele and type 2 diabetes on cognition. Potential mechanisms may involve PP-related weight loss and centrally mediated effects of PP on cognition. These findings remain to be validated in other studies

Association of Pancreatic Polypeptide with Mild Cognitive Impairment Varies by APOE ε4 Allele

© 2015 Roberts, Aakre, Cha, Kremers, Mielke, Velgos, Geda, Knopman and Petersen. We conducted a preliminary case-control investigation of the association of pancreatic polypeptide (PP) with mild cognitive impairment (MCI) in 202 MCI cases (mean age, 81.6 years) and 202 age- and sex-matched cognitively normal controls in the Mayo Clinic Study of Aging. Plasma PP was measured and examined as the natural logarithm (continuous) and dichotomized at the median. The OR (95% CI) of MCI increased with increasing PP [1.46 (1.04-2.05)]. There was a negative interaction of PP with apolipoprotein E (APOE) ε4 allele; compared to the reference group (no APOE ε4 allele and low PP), the OR (95% CI) for combinations of ε4 and PP were: 2.64 (1.39-5.04) for APOE ε4 plus low PP; 2.09 (1.27-3.45) for no APOE ε4 plus high PP; and 1.91 (1.04-3.53) for no APOE ε4 plus high PP (P for interaction = 0.017). There was also a trend toward a negative interaction with type 2 diabetes (P for interaction = 0.058). Compared to no diabetes and low PP, the OR (95% CI) was 3.02 (1.22-7.46) for low PP plus diabetes but 1.80 (1.01-3.22) for high PP plus diabetes. Participants with high PP had a greater mean (SD) weight loss (kilograms per decade) than persons with low PP [-2.27 (4.07) vs. -1.61 (5.24); P = 0.016]. MCI cases had a non-significantly greater weight loss per decade compared to controls. These findings suggest that high PP alone or jointly with APOE ε4 allele or type 2 diabetes is associated with MCI, and that high PP may mitigate some effects of APOE ε4 allele and type 2 diabetes on cognition. Potential mechanisms may involve PP-related weight loss and centrally mediated effects of PP on cognition. These findings remain to be validated in other studies

Decline in weight and incident mild cognitive impairment Mayo Clinic study of aging

Copyright 2016 American Medical Association. All rights reserved. IMPORTANCE: Unintentional weight loss has been associated with risk of dementia. Because mild cognitive impairment (MCI) is a prodromal stage for dementia, we sought to evaluate whether changesin weight and body mass index (BMI) may predict incident MCI. OBJECTIVE: To investigate the association of change in weight and BMI with risk of MCI. DESIGN, SETTING, AND PARTICIPANTS: A population-based, prospective study of participants 70 years of age or older from the Mayo Clinic Study of Aging, which was initiated on October 1, 2004. Maximum weight and height in midlife (40-65 years of age) were retrospectively ascertained from the medical records of participants using a medical records-linkage system. The statistical analyses were performed between January and November 2015. MAINOUTCOMESAND MEASURES: Participants were evaluated for cognitive outcomes of normal cognition, MCI, or dementia at baseline and prospectively assessed for incident events at each 15-month evaluation. The association of rate of change in weight and BMI with risk of MCI was investigated using proportional hazards models. RESULTS: Over a mean follow-up of 4.4 years, 524 of 1895 cognitively normal participants developed incident MCI (50.3% were men; mean age, 78.5 years). The mean (SD) rate of weight change per decade from midlife to study entry was greater for participants who developed incident MCI vs those who remained cognitively normal (-2.0 [5.1] vs-1.2 [4.9] kg; P =.006). A greater decline in weight per decade was associated with an increased risk of incident MCI (hazard ratio [HR], 1.04 [95% CI, 1.02-1.06]; P \u3c.001) after adjusting for sex, education, and apolipoprotein E (APOE) e4 allele. A weight loss of 5 kg per decade corresponds to a 24% increase in risk of MCI (HR, 1.24). A higher decrease in BMI per decade was also associated with incident MCI (HR, 1.08 [95% CI, 1.03-1.13]; P =.003). CONCLUSIONS AND RELEVANCE: These findings suggest that increasing weight loss per decade from midlife to late life is a marker for MCI and may help identify persons at increased risk for MCI

Informant-based hearing difficulties and the risk for mild cognitive impairment and dementia

© 2019 The Author(s) 2019. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: [email protected]. Background: hearing loss has been associated with mild cognitive impairment (MCI) and dementia. Studies have not assessed whether hearing difficulties (HD) that interfere with daily activities as reported by partners can be a marker for increased risk for cognitive decline and impairment. Objective: to assess the cross-sectional and longitudinal associations between informant-based HD, which interfere with daily activities and the risk for MCI and dementia. Methods: the study included 4812 participants without dementia, enrolled in the Mayo Clinic Study of Aging (mean age (SD) 73.7 (9.6) years) with cognitive evaluation and informant-based report on participant\u27s HD that interfere significantly with daily activities at baseline and for every 15 months. Cox proportional hazards models (utilising time-dependent HD status and age as the time scale) were used to examine HD and the risk for MCI or dementia, and mixed-effects models (allowing for random subject-specific intercepts and slopes) were used to examine the relationship between HD and cognitive decline. Results: about, 981 participants had HD and 612 (12.7%) had prevalent MCI at baseline; 759 participants developed incident MCI and 273 developed incident dementia. In cognitively unimpaired participants at baseline, those with HD had higher risk for MCI (hazard ratio [HR] = 1.29, 95% confidence interval [CI] (1.10, 1.51), P = 0.002; adjusting for sex, years of education). In participants without dementia, those with HD had higher risk for dementia (HR: 1.39, 95% CI, (1.08-1.79), P = 0.011; adjusting sex and education). In individuals with MCI, HD was associated with modestly greater cognitive decline. Conclusions: informant-based HD was associated with increased risk for MCI and dementia

Mediterranean diet, micronutrients and macronutrients, and MRI measures of cortical thickness

INTRODUCTION: The Mediterranean diet (MeDi) is associated with reduced risk of cognitive impairment, but it’s unclear whether it’s associated with better brain imaging biomarkers. METHODS: Among 672 cognitively normal participants (mean age: 79.8 years, 52.5% men), we investigated associations of MeDi score and MeDi components with magnetic resonance imaging measures of cortical thickness for the 4 lobes separately and averaged (average lobar). RESULTS: Higher MeDi score was associated with larger frontal, parietal, occipital, and average lobar cortical thickness. Higher legume and fish intakes were associated with larger cortical thickness: legumes with larger superior parietal, inferior parietal, precuneus, parietal, occipital, lingual, and fish with larger precuneus, superior parietal, posterior cingulate, parietal, inferior parietal. Higher carbohydrate and sugar intakes were associated with lower entorhinal cortical thickness. DISCUSSION: In this sample of elderly persons, higher adherence to MeDi was associated with larger cortical thickness. These cross-sectional findings require validation in prospective studies

Mediterranean diet, micronutrients and macronutrients, and MRI measures of cortical thickness

© 2016 the Alzheimer\u27s Association Introduction The Mediterranean diet (MeDi) is associated with reduced risk of cognitive impairment, but it is unclear whether it is associated with better brain imaging biomarkers. Methods Among 672 cognitively normal participants (mean age, 79.8 years, 52.5% men), we investigated associations of MeDi score and MeDi components with magnetic resonance imaging measures of cortical thickness for the four lobes separately and averaged (average lobar). Results Higher MeDi score was associated with larger frontal, parietal, occipital, and average lobar cortical thickness. Higher legume and fish intakes were associated with larger cortical thickness: legumes with larger superior parietal, inferior parietal, precuneus, parietal, occipital, lingual, and fish with larger precuneus, superior parietal, posterior cingulate, parietal, and inferior parietal. Higher carbohydrate and sugar intakes were associated with lower entorhinal cortical thickness. Discussion In this sample of elderly persons, higher adherence to MeDi was associated with larger cortical thickness. These cross-sectional findings require validation in prospective studies

Multimorbidity and risk of mild cognitive impairment

© 2015, Copyright the Authors Journal compilation © 2015, The American Geriatrics Society. Objectives To determine the association between multiple chronic conditions and risk of incident mild cognitive impairment (MCI) and dementia. Design Prospective cohort study. Setting Olmsted County, Minnesota. Participants Cognitively normal individuals (N = 2,176) enrolled in the Mayo Clinic Study of Aging (MCSA). Measurements Participants were randomly selected from the community, evaluated by a physician, and underwent neuropsychometric testing at baseline and at 15-month intervals to assess diagnoses of MCI and dementia. Information on International Classification of Diseases, Ninth Revision codes for chronic conditions in the 5 years before enrollment was electronically captured using the Rochester Epidemiology Project medical records linkage system. Multimorbidity was defined as having two or more chronic conditions, and the association between multimorbidity and MCI and dementia was examined using Cox proportional hazards models. Results Of 2,176 cognitively normal participants (mean age ± standard deviation 78.5 ± 5.2; 50.6% male), 1,884 (86.6%) had multimorbidity. The risk of MCI or dementia was higher in persons with multimorbidity (hazard ratio (HR) = 1.38, 95% confidence interval (CI) = 1.05-1.82) than in those with one or no chronic condition. The HR was of greater magnitude in persons with four or more conditions (HR = 1.61, 95% CI = 1.21-2.13) than in those with two or three conditions (HR = 1.03, 95% CI = 0.76-1.39) and for men with multimorbidity(HR = 1.53, 95% CI = 1.01-2.31) than for women with multimorbidity (HR = 1.20, 95% CI = 0.83-1.74), compared to those with one or no chronic condition. Conclusion In older adults, having multiple chronic conditions is associated with greater risk of MCI and dementia. This is consistent with the hypothesis that multiple etiologies may contribute to MCI and late-life dementia. Preventing chronic diseases may be beneficial in delaying or preventing MCI and dementia

Multimorbidity and neuroimaging biomarkers among cognitively normal persons

© 2016 American Academy of Neurology. Objective: To assess the cross-sectional association between multimorbidity and imaging biomarkers of brain pathology in the population-based Mayo Clinic Study of Aging (MCSA). Methods: The study consisted of 1,449 MCSA participants who were cognitively normal at the time of MRI. A subset of the participants also had 11C-Pittsburgh compound B (n 5 689) and 18fluorodeoxyglucose (n 5 688) PET scans available. Information on multimorbidity (defined as 2 chronic conditions) in the 5 years prior to the first imaging study was captured from the medical record using ICD-9 codes for chronic conditions and the Rochester Epidemiology Project medical records linkage system. The cross-sectional association of multimorbidity and imaging biomarkers was examined using logistic and linear regression models. Results: Among 1,449 cognitively normal participants (mean age 79 years; 50.9% men), 85.4% had multimorbidity (2 chronic conditions). Multimorbidity and severe multimorbidity (4 chronic conditions) were associated with abnormal Alzheimer disease (AD) signature meta-region of interest (meta-ROI) 18F-FDG hypometabolism (odds ratio [OR] 2.03; 95% confidence interval [CI] 1.10-3.77 and OR 2.22; 95% CI 1.18-4.16, respectively), and with abnormal AD signature MRI cortical thickness (OR 1.53; 95% CI 1.09-2.16 and OR 1.76; 95% CI 1.24-2.51, respectively), but was not associated with amyloid accumulation. Conclusions: Multimorbidity was associated with brain pathology through mechanisms independent of amyloid deposition and such neuronal injury and pathology was present before any symptomatic evidence of cognitive impairment. Longitudinal follow-up will provide insights into potential causal associations of multimorbidity with changes in brain pathology