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

Genetic loci influencing kidney function and chronic kidney disease

Using genome-wide association, we identify common variants at 2p12-p13, 6q26, 17q23 and 19q13 associated with serum creatinine, a marker of kidney function (P = 10 10 to 10 15). Of these, rs10206899 (near NAT8, 2p12-p13) and rs4805834 (near SLC7A9, 19q13) were also associated with chronic kidney disease (P = 5.0 × 10 5 and P = 3.6 × 10 4, respectively). Our findings provide insight into metabolic, solute and drug-transport pathways underlying susceptibility to chronic kidney disease

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

The significance of tumour deposits in rectal cancer after neoadjuvant therapy: a systematic review and meta-analysis

Contains fulltext : 215730pub.pdf (publisher's version ) (Closed access)BACKGROUND: Tumour deposits (TDs) are a poor prognostic marker in colorectal cancer, but their significance after neoadjuvant chemoradiotherapy is less certain because this group of patients is excluded in most studies. Post-treatment TD might even be a sign of tumour response. No previous reviews have assessed outcomes in this group. MATERIALS AND METHODS: A systematic review and meta-analysis was undertaken according to Preferred Reporting for Systematic Reviews and Meta-Analyses guidelines to determine the relevance of post-treatment TD. Inclusion criteria were studies assessing TD in patients who had undergone pre-operative treatment with radiotherapy and/or chemotherapy and reporting prevalence and survival outcomes. Studies that did not include histological review of cases were excluded. RESULTS: Eight studies and 1283 patients were included in the review. Prevalence of TDs varied from 11.8% to 44.2% (mean 23.7%), similar to untreated patients. The presence of TDs after chemoradiotherapy was associated with invasion depth, lymph node involvement, perineural invasion and synchronous metastases. The pooled hazard ratio for 5-year adverse disease-free survival was 2.3 (95% confidence interval [CI]: 1.8-2.9), and that for overall survival was 2.5 (95% CI: 1.9-3.3). One study showed a survival benefit with adjuvant therapy in the TD-positive group. CONCLUSIONS: In analogy with untreated patients, the presence of TDs in patients with rectal cancer after neoadjuvant treatment is associated with advanced disease and a poor outcome