Assessment of a polygenic hazard score for the onset of pre-clinical Alzheimer’s disease

Background: With a growing number of loci associated with late-onset (sporadic) Alzheimer’s disease (AD), the polygenic contribution to AD is now well established. The development of polygenic risk score approaches have shown promising results for identifying individuals at higher risk of developing AD, thereby facilitating the development of preventative and therapeutic strategies. A polygenic hazard score (PHS) has been proposed to quantify age-specific genetic risk for AD. In this study, we assessed the predictive power and transferability of this PHS in an independent cohort, to support its clinical utility. Results: Using genotype and imaging data from 780 individuals enrolled in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study, we investigated associations between the PHS and several AD-related traits, including 1) cross-sectional Aβ-amyloid (Aβ) deposition, 2) longitudinal brain atrophy, 3) longitudinal cognitive decline, 4) age of onset. Except in the cognitive domain, we obtained results that were consistent with previously published findings. The PHS was associated with increased Aβ burden, faster regional brain atrophy and an earlier age of onset. Conclusion: Overall, the results support the predictive power of a PHS, however, with only marginal improvement compared to apolipoprotein E alone

Using imputation to provide harmonized longitudinal measures of cognition across AIBL and ADNI

To improve understanding of Alzheimer’s disease, large observational studies are needed to increase power for more nuanced analyses. Combining data across existing observational studies represents one solution. However, the disparity of such datasets makes this a non-trivial task. Here, a machine learning approach was applied to impute longitudinal neuropsychological test scores across two observational studies, namely the Australian Imaging, Biomarkers and Lifestyle Study (AIBL) and the Alzheimer\u27s Disease Neuroimaging Initiative (ADNI) providing an overall harmonised dataset. MissForest, a machine learning algorithm, capitalises on the underlying structure and relationships of data to impute test scores not measured in one study aligning it to the other study. Results demonstrated that simulated missing values from one dataset could be accurately imputed, and that imputation of actual missing data in one dataset showed comparable discrimination (p \u3c 0.001) for clinical classification to measured data in the other dataset. Further, the increased power of the overall harmonised dataset was demonstrated by observing a significant association between CVLT-II test scores (imputed for ADNI) with PET Amyloid-β in MCI APOE-ε4 homozygotes in the imputed data (N = 65) but not for the original AIBL dataset (N = 11). These results suggest that MissForest can provide a practical solution for data harmonization using imputation across studies to improve power for more nuanced analyses

Multicenter Collaborative Study to Optimize Mass Spectrometry Workflows of Clinical Specimens

The foundation for integrating mass spectrometry (MS)-based proteomics into systems medicine is the development of standardized start-to-finish and fit-for-purpose workflows for clinical specimens. An essential step in this pursuit is to highlight the common ground in a diverse landscape of different sample preparation techniques and liquid chromatography-mass spectrometry (LC-MS) setups. With the aim to benchmark and improve the current best practices among the proteomics MS laboratories of the CLINSPECT-M consortium, we performed two consecutive round-robin studies with full freedom to operate in terms of sample preparation and MS measurements. The six study partners were provided with two clinically relevant sample matrices: plasma and cerebrospinal fluid (CSF). In the first round, each laboratory applied their current best practice protocol for the respective matrix. Based on the achieved results and following a transparent exchange of all lab-specific protocols within the consortium, each laboratory could advance their methods before measuring the same samples in the second acquisition round. Both time points are compared with respect to identifications (IDs), data completeness, and precision, as well as reproducibility. As a result, the individual performances of participating study centers were improved in the second measurement, emphasizing the effect and importance of the expert-driven exchange of best practices for direct practical improvements

Impaired cardiac contractile function in arginine:glycine amidinotransferase knockout mice devoid of creatine is rescued by homoarginine but not creatine

Aims: Creatine buffers cellular adenosine triphosphate (ATP) via the creatine kinase reaction. Creatine levels are reduced in heart failure, but their contribution to pathophysiology is unclear. Arginine:glycine amidinotransferase (AGAT) in the kidney catalyses both the first step in creatine biosynthesis as well as homoarginine (HA) synthesis. AGAT-/- mice fed a creatine-free diet have a whole body creatine-deficiency. We hypothesized that AGAT-/- mice would develop cardiac dysfunction and rescue by dietary creatine would imply causality. Methods and results: Withdrawal of dietary creatine in AGAT-/- mice provided an estimate of myocardial creatine efflux of ∼2.7%/day; however, in vivo cardiac function was maintained despite low levels of myocardial creatine. Using AGAT-/- mice naïve to dietary creatine we confirmed absence of phosphocreatine in the heart, but crucially, ATP levels were unchanged. Potential compensatory adaptations were absent, AMPK was not activated and respiration in isolated mitochondria was normal. AGAT-/- mice had rescuable changes in body water and organ weights suggesting a role for creatine as a compatible osmolyte. Creatine-naïve AGAT-/- mice had haemodynamic impairment with low LV systolic pressure and reduced inotropy, lusitropy, and contractile reserve. Creatine supplementation only corrected systolic pressure despite normalization of myocardial creatine. AGAT-/- mice had low plasma HA and supplementation completely rescued all other haemodynamic parameters. Contractile dysfunction in AGAT-/- was confirmed in Langendorff perfused hearts and in creatine-replete isolated cardiomyocytes, indicating that HA is necessary for normal cardiac function. Conclusions: Our findings argue against low myocardial creatine per se as a major contributor to cardiac dysfunction. Conversely, we show that HA deficiency can impair cardiac function, which may explain why low HA is an independent risk factor for multiple cardiovascular diseases

A systematic review of longitudinal studies on the association between depression and smoking in adolescents

<p>Abstract</p> <p>Background</p> <p>It is well-established that smoking and depression are associated in adolescents, but the temporal ordering of the association is subject to debate.</p> <p>Methods</p> <p>Longitudinal studies in English language which reported the onset of smoking on depression in non clinical populations (age 13-19) published between January 1990 and July 2008 were selected from PubMed, OVID, and PsychInfo databases. Study characteristics were extracted. Meta-analytic pooling procedures with random effects were used.</p> <p>Results</p> <p>Fifteen studies were retained for analysis. The pooled estimate for smoking predicting depression in 6 studies was 1.73 (95% CI: 1.32, 2.40; p < 0.001). The pooled estimate for depression predicting smoking in 12 studies was 1.41 (95% CI: 1.21, 1.63; p < 0.001). Studies that used clinical measures of depression were more likely to report a bidirectional effect, with a stronger effect of depression predicting smoking.</p> <p>Conclusion</p> <p>Evidence from longitudinal studies suggests that the association between smoking and depression is bidirectional. To better estimate these effects, future research should consider the potential utility of: (a) shorter intervals between surveys with longer follow-up time, (b) more accurate measurement of depression, and (c) adequate control of confounding.</p

Dreams and nightmares of liberal international law: capitalist accumulation, natural rights and state hegemony

This article develops a line of theorising the relationship between peace, war and commerce and does so via conceptualising global juridical relations as a site of contestation over questions of economic and social justice. By sketching aspects of a historical interaction between capitalist accumulation, natural rights and state hegemony, the article offers a critical account of the limits of liberal international law, and attempts to recover some ground for thinking about the emancipatory potential of international law more generally