Comprehensive analysis of epigenetic clocks reveals associations between disproportionate biological ageing and hippocampal volume

The concept of age acceleration, the difference between biological age and chronological age, is of growing interest, particularly with respect to age-related disorders, such as Alzheimer’s Disease (AD). Whilst studies have reported associations with AD risk and related phenotypes, there remains a lack of consensus on these associations. Here we aimed to comprehensively investigate the relationship between five recognised measures of age acceleration, based on DNA methylation patterns (DNAm age), and cross-sectional and longitudinal cognition and AD-related neuroimaging phenotypes (volumetric MRI and Amyloid-β PET) in the Australian Imaging, Biomarkers and Lifestyle (AIBL) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Significant associations were observed between age acceleration using the Hannum epigenetic clock and cross-sectional hippocampal volume in AIBL and replicated in ADNI. In AIBL, several other findings were observed cross-sectionally, including a significant association between hippocampal volume and the Hannum and Phenoage epigenetic clocks. Further, significant associations were also observed between hippocampal volume and the Zhang and Phenoage epigenetic clocks within Amyloid-β positive individuals. However, these were not validated within the ADNI cohort. No associations between age acceleration and other Alzheimer’s disease-related phenotypes, including measures of cognition or brain Amyloid-β burden, were observed, and there was no association with longitudinal change in any phenotype. This study presents a link between age acceleration, as determined using DNA methylation, and hippocampal volume that was statistically significant across two highly characterised cohorts. The results presented in this study contribute to a growing literature that supports the role of epigenetic modifications in ageing and AD-related phenotypes

Uncovering the heterogeneity and temporal complexity of neurodegenerative diseases with Subtype and Stage Inference

The heterogeneity of neurodegenerative diseases is a key confound to disease understanding and treatment development, as study cohorts typically include multiple phenotypes on distinct disease trajectories. Here we introduce a machine-learning technique\u2014Subtype and Stage Inference (SuStaIn)\u2014able to uncover data-driven disease phenotypes with distinct temporal progression patterns, from widely available cross-sectional patient studies. Results from imaging studies in two neurodegenerative diseases reveal subgroups and their distinct trajectories of regional neurodegeneration. In genetic frontotemporal dementia, SuStaIn identifies genotypes from imaging alone, validating its ability to identify subtypes; further the technique reveals within-genotype heterogeneity. In Alzheimer\u2019s disease, SuStaIn uncovers three subtypes, uniquely characterising their temporal complexity. SuStaIn provides fine-grained patient stratification, which substantially enhances the ability to predict conversion between diagnostic categories over standard models that ignore subtype (p = 7.18 7 10 124 ) or temporal stage (p = 3.96 7 10 125 ). SuStaIn offers new promise for enabling disease subtype discovery and precision medicine

Management and organizational assessments: a review of selected organizations

This report is part of a larger project designed to assist the NRC in its responsibilities for assessing the management and organization of utilities applying for an operating license for a nuclear power plant. This report reviews the processes and criteria used by other organizations that conduct management and organization audits and evaluations. It was undertaken in order to provide data and a basis for future analysis by taking a comparative perspective. When considering changes in criteria and procedures as the NRC is doing, a standard benchmark is the performance of other organizations that are similarly situated. It was our goal to directly inform the NRC about the activities of other organizations so that a reconsideration of NRC activities could benefit from the perspective of organizations with a longer, broader, and different experience than the NRC has in the management and organization area. Data collected for this report has provided useful information in designing organization and administration guidelines and assessment procedures for consideration by the NRC

Effect of replacing a portion of inorganic chloride trace minerals with trace mineral amino acid complexes

ABSTRACT: The objective was to determine whether replacing a portion of inorganic chloride trace minerals and cobalt carbonate in the diet with AA complexes of trace minerals and cobalt glucoheptonate will improve lactating cow performance, feed efficiency, and calf performance. In a clinical trial, 69 Holstein cows entering second lactation and greater were randomly assigned to 1 of 2 treatments, with the total dietary trace mineral concentration the same between treatments, starting 1 wk after dry off (50 to 57 d before expected parturition) until 154 d in milk (DIM): (1) an inorganic chloride trace mineral (ITM) blend consisting of Zn (75 mg/kg), Mn (65 mg/kg), and Cu (10 mg/kg) as hydroxychlorides and Co (1 mg/kg) as carbonate (n = 37) or (2) partial replacement of ITM with AA complexes of Zn (40 mg/kg), Mn (20 mg/kg), and Cu (3.5 mg/kg) and Co glucoheptonate (1 mg/kg; AATM; Availa-Dairy, Zinpro Corp.; n = 32). Dry matter intake (DMI) was recorded daily from enrollment through wk 8, and milk yields were recorded daily from calving through wk 22. Milk composition and body weights (BW) were collected weekly. Serum samples were analyzed for albumin (Alb), cholesterol (Chol), total bilirubin (Bili), aspartate aminotransferase (AST), haptoglobin, β-hydroxybutyrate (BHB), and Ca. A liver health index (LHI) was calculated based on Bili, Chol, and Alb concentrations. A liver functionality index (LFI) was calculated to standardize changes in Alb, Chol, and Bili from 4 to 29 DIM. Greater LHI and LFI indicate better health status. Colostrum was analyzed for IgG and Brix, and calf serum was analyzed for IgG. Calf growth was monitored through 9 wk of age (AATM: n = 12, ITM: n = 10). Data were analyzed using SAS software with mixed effects models and repeated-measures analysis, when applicable. Survival analysis for pregnancy by 154 DIM was analyzed by Cox proportional and Kaplan-Meier hazards models. Disorder incidence was tested with Fisher's exact test. Prepartum DMI as a percent of BW was lower in cows fed AATM and not significant postpartum. Cows fed AATM produced more milk from wk 1 to 8 and from wk 1 to 22. Energy-corrected milk yield and colostrum measures did not significantly differ between treatments. A treatment by time interaction was seen for AST and BHB; cows fed AATM tended to have lower AST concentrations at 28 DIM and lower concentrations in BHB through 29 DIM, though not statistically significant. Cows fed AATM had greater LHI at 4 DIM. Haptoglobin, Ca, LFI, hazard of pregnancy, risk to first service, survival curves, or services per pregnancy did not significantly differ. Calf serum IgG and birth weight did not significantly differ between treatments. Calves from dams fed AATM had greater average daily gain than calves from dams fed ITM. Overall, cows fed AATM during the dry period and early lactation had improved postpartum performance and potential health improvements

Effect of Prepartum DCAD Strategy and Level of Dietary Calcium on Postpartum Calcium Status and Performance of Multiparous Holstein Cows

Periparturient hypocalcemia can be mitigated by reducing prepartum dietary DCAD; however, neither the extent of DCAD adjustment nor the level of dietary Ca fed with negative DCAD have been evaluated fully. This project aimed to compare the effects of two levels of prepartum dietary anion supplementation (urinary pH), two levels of dietary calcium, and the interactions, on parameters of calcium metabolism, health, and milk performance of transition dairy cows

Central artery stiffness, baroreflex sensitivity, and brain white matter neuronal fiber integrity in older adults

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