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

The role of layer-induced anisotropy in seismic exploration

184In this thesis we focus on anisotropy caused by fine layering. We analyse the conditions that must be satisfied so that fine layering is equivalent to anisotropy. In the long-wavelength (or quasi-static) approximation an interval of thickness H, consisting of a sequence of layers, is effectively homogeneous and anisotropic to seismic wave propagation. This approximation implies that H is much smaller than the seismic wavelength A. Closer inspection of this approximation shows that the degree of equivalence depends on several parameters. The equivalence is exact for infinitely long wavelengths. It is also exact (for all wavelengths) for those waves which are not back-scattered at the interfaces between the layers. This is the case when reflection coefficients are zero. We use a simple model where the interval of thickness H consists of a N times repeated set of two layers. These two layers form one period, the whole interval consists of N periods. The wave field that propagates through this sequence oflayers, consists of the sum of the primary wave and all the multiples. The effective medium for a given wave number depends on the interference of primary and multiples. For infinitely thin layers this results in an effectively homogeneous medium, with a pseudo-primary that is delayed compared to the primary wave

Underground sound. application of seismic waves

J.E. White. methods in geochemistry and geophysics, 18, Elsevier, Amsterdam, 1983, xvi + 253 pp., US $59.50 (USA and Canada), Dfl. 140.00 (hard cover

. . . \u27twas ten to one; And yet we ventured. . . : P300 and Decision Making

In some situations subjects\u27 predictions of future events do not accurately reflect the subjective probability associated with these events. We set up such a situation by manipulating the payoff structure in a prediction paradigm, and found that P300 provides an index of the processes responsible for subjective probability, or expectancy, not obtainable from overt predictions. Sixteen subjects were required to predict, on each trial, whether a 1, 2, or 3 would appear on a display. The numbers appeared randomly with probabilities .45, .10, and .45, respectively. In one condition subjects were given bonuses according to an all‐or‐none payoff function in which they received one cent if they predicted correctly, and nothing if they were incorrect. In a second condition bonuses were determined by a linear payoff function in which subjects were paid one cent if they predicted correctly, and one‐half cent if they were off by one (e.g., predict 1 and 2 appears). After each condition subjects estimated the actual number of stimuli presented. These estimates were the same for both conditions, although predictions differed radically, with 2 predicted much more frequently in the linear condition. P300 area was largest for the rare event (2), and the relationship between P300 and probability was unaffected by payoffs. Our design did introduce differences between conditions in the overall “riskiness’ of predictions, and the strategies adopted by most subjects also resulted in differences in the salience, or task relevance, of the feedback stimuli. These differences resulted in an overall increase in P300 in the all‐or‐none condition. A relationship also emerged between the subjects\u27 strategies and their ERPs. Subjects who adopted more effective strategies responded differentially to feedback from high and low risk predictions, whereas the others did not

Contrasting Trans-Atlantic Migratory Routes of Nearctic Purple SandpipersCalidris maritimaAssociated with Low Pressure Systems in Spring and Winter

Bird migration is generally scheduled to avoid other energetically expensive events in the annual cycle (e.g. moult) and seasons when survival can be difficult (e.g. northern winters). Purple Sandpipers winter at relatively high latitudes compared to other waders. It is suspected that the majority that winter in Britain and Ireland originate from Canada, but there is no primary evidence of their breeding grounds and migratory routes. These birds, characterised by their long bills, start to arrive in Britain and Ireland in late October/early November, after completing their post-nuptial moult at an unknown location. Fifty geolocators were attached to Purple Sandpipers in northern Scotland and southwest Ireland and we established for the first time their Canadian origin (Baffin Island and Devon Island), migration routes and post-nuptial moulting areas. Spring departure from Scotland and Ireland took place mainly in late May, followed by staging in Iceland and/or southwest Greenland before reaching the breeding grounds. Those that staged in Iceland departed earlier than those that flew directly to Greenland. Post-nuptial moulting areas were in southern Baffin Island, northern Quebec/Labrador (the Hudson Strait), and southwest Greenland. Migration from Baffin Island and Labrador took place during late October – early November, and during mid to late December from Greenland, usually in a single trans-Atlantic flight. Therefore, this migration was scheduled at a time when most other wader species are already on their wintering grounds. No birds staged in Iceland on the return trip. The flight from Baffin Island to Scotland and Ireland was accomplished in about 2.5 days at an average speed of about 1400 km per day. Freezing of coastal waters may be the reason for the eventual departure from the Hudson Strait. The more northerly route via Iceland, taken in spring by most birds, and the more southerly route in early winter were associated with seasonal shifts in the Atlantic low pressure systems (depressions) whose anti-clockwise wind-flows would have assisted flights