Plasma proteomic associations with genetics and health in the UK Biobank.

The Pharma Proteomics Project is a precompetitive biopharmaceutical consortium characterizing the plasma proteomic profiles of 54,219 UK Biobank participants. Here we provide a detailed summary of this initiative, including technical and biological validations, insights into proteomic disease signatures, and prediction modelling for various demographic and health indicators. We present comprehensive protein quantitative trait locus (pQTL) mapping of 2,923 proteins that identifies 14,287 primary genetic associations, of which 81% are previously undescribed, alongside ancestry-specific pQTL mapping in non-European individuals. The study provides an updated characterization of the genetic architecture of the plasma proteome, contextualized with projected pQTL discovery rates as sample sizes and proteomic assay coverages increase over time. We offer extensive insights into trans pQTLs across multiple biological domains, highlight genetic influences on ligand-receptor interactions and pathway perturbations across a diverse collection of cytokines and complement networks, and illustrate long-range epistatic effects of ABO blood group and FUT2 secretor status on proteins with gastrointestinal tissue-enriched expression. We demonstrate the utility of these data for drug discovery by extending the genetic proxied effects of protein targets, such as PCSK9, on additional endpoints, and disentangle specific genes and proteins perturbed at loci associated with COVID-19 susceptibility. This public-private partnership provides the scientific community with an open-access proteomics resource of considerable breadth and depth to help to elucidate the biological mechanisms underlying proteo-genomic discoveries and accelerate the development of biomarkers, predictive models and therapeutics1.

Differences and commonalities in the genetic architecture of protein quantitative trait loci in European and Arab populations.

Polygenic scores (PGS) can identify individuals at risk of adverse health events and guide genetics-based personalized medicine. However, it is not clear how well PGS translate between different populations, limiting their application to well-studied ethnicities. Proteins are intermediate traits linking genetic predisposition and environmental factors to disease, with numerous blood circulating protein levels representing functional readouts of disease-related processes. We hypothesized that studying the genetic architecture of a comprehensive set of blood-circulating proteins between a European and an Arab population could shed fresh light on the translatability of PGS to understudied populations. We therefore conducted a genome-wide association study with whole-genome sequencing data using 1301 proteins measured on the SOMAscan aptamer-based affinity proteomics platform in 2935 samples of Qatar Biobank and evaluated the replication of protein quantitative traits (pQTLs) from European studies in an Arab population. Then, we investigated the colocalization of shared pQTL signals between the two populations. Finally, we compared the performance of protein PGS derived from a Caucasian population in a European and an Arab cohort. We found that the majority of shared pQTL signals (81.8%) colocalized between both populations. About one-third of the genetic protein heritability was explained by protein PGS derived from a European cohort, with protein PGS performing ~20% better in Europeans when compared to Arabs. Our results are relevant for the translation of PGS to non-Caucasian populations, as well as for future efforts to extend genetic research to understudied populations.

The metabolome-wide signature of major depressive disorder.

Major Depressive Disorder (MDD) is a common, frequently chronic condition characterized by substantial molecular alterations and pathway dysregulations. Single metabolite and targeted metabolomics platforms have revealed several metabolic alterations in depression, including energy metabolism, neurotransmission, and lipid metabolism. More comprehensive coverage of the metabolome is needed to further specify metabolic dysregulations in depression and reveal previously untargeted mechanisms. Here, we measured 820 metabolites using the metabolome-wide Metabolon platform in 2770 subjects from a large Dutch clinical cohort with extensive clinical phenotyping (1101 current MDD, 868 remitted MDD, 801 healthy controls) at baseline, which were repeated in 1805 subjects at 6-year follow up (327 current MDD, 1045 remitted MDD, 433 healthy controls). MDD diagnosis was based on DSM-IV psychiatric interviews. Depression severity was measured with the Inventory of Depressive Symptomatology Self-report. Associations between metabolites and MDD status and depression severity were assessed at baseline and at 6-year follow-up. At baseline, 139 and 126 metabolites were associated with current MDD status and depression severity, respectively, with 79 overlapping metabolites. Adding body mass index and lipid-lowering medication to the models changed results only marginally. Among the overlapping metabolites, 34 were confirmed in internal replication analyses using 6-year follow-up data. Downregulated metabolites were enriched with long-chain monounsaturated (P = 6.7e-07) and saturated (P = 3.2e-05) fatty acids; upregulated metabolites were enriched with lysophospholipids (P = 3.4e-4). Mendelian randomization analyses using genetic instruments for metabolites (N = 14,000) and MDD (N = 800,000) showed that genetically predicted higher levels of the lysophospholipid 1-linoleoyl-GPE (18:2) were associated with greater risk of depression. The identified metabolome-wide profile of depression indicated altered lipid metabolism with downregulation of long-chain fatty acids and upregulation of lysophospholipids, for which causal involvement was suggested using genetic tools. This metabolomics signature offers a window on depression pathophysiology and a potential access point for the development of novel therapeutic approaches.

Comparative brain metabolomics reveals shared and distinct metabolic alterations in Alzheimer's disease and progressive supranuclear palsy.

BACKGROUND: Metabolic dysregulation is a hallmark of neurodegenerative diseases, including Alzheimer's disease (AD) and progressive supranuclear palsy (PSP). Although metabolic dysregulation is a common link between these two tauopathies, a comprehensive brain metabolic comparison of the diseases has not yet been performed. METHODS: We analyzed 342 postmortem brain samples from the Mayo Clinic Brain Bank and examined 658 metabolites in the cerebellar cortex and the temporal cortex between the two tauopathies. RESULTS: Our findings indicate that both diseases display oxidative stress associated with lipid metabolism, mitochondrial dysfunction linked to lysine metabolism, and an indication of tau-induced polyamine stress response. However, specific to AD, we detected glutathione-related neuroinflammation, deregulations of enzymes tied to purines, and cognitive deficits associated with vitamin B. DISCUSSION: Our findings underscore vast alterations in the brain's metabolome, illuminating shared neurodegenerative pathways and disease-specific traits in AD and PSP. HIGHLIGHTS: First high-throughput metabolic comparison of Alzheimer's diesease (AD) versus progressive supranuclear palsy (PSP) in brain tissue. Cerebellar cortex (CER) shows substantial AD-related metabolic changes, despite limited proteinopathy. AD impacts both CER and temporal cortex (TCX); PSP's changes are primarily in CER. AD and PSP share metabolic alterations despite major pathological differences.

maplet: an extensible R toolbox for modular and reproducible metabolomics pipelines.

This article presents maplet, an open-source R package for the creation of highly customizable, fully reproducible statistical pipelines for metabolomics data analysis. It builds on the SummarizedExperiment data structure to create a centralized pipeline framework for storing data, analysis steps, results and visualizations. maplet's key design feature is its modularity, which offers several advantages, such as ensuring code quality through the maintenance of individual functions and promoting collaborative development by removing technical barriers to code contribution. With over 90 functions, the package includes a wide range of functionalities, covering many widely used statistical approaches and data visualization techniques. AVAILABILITY AND IMPLEMENTATION: The maplet package is implemented in R and freely available at https://github.com/krumsieklab/maplet.

Metabolomic and inflammatory signatures of symptom dimensions in major depression.

BACKGROUND: Major depressive disorder (MDD) is a highly heterogenous disease, both in terms of clinical profiles and pathobiological alterations. Recently, immunometabolic dysregulations were shown to be correlated with atypical, energy-related symptoms but less so with the Melancholic or Anxious distress symptom dimensions of depression in The Netherlands Study of Depression and Anxiety (NESDA) study. In this study, we aimed to replicate these immunometabolic associations and to characterize the metabolomic correlates of each of the three MDD dimensions. METHODS: Using three clinical rating scales, Melancholic, and Anxious distress, and Immunometabolic (IMD) dimensions were characterized in 158 patients who participated in the Predictors of Remission to Individual and Combined Treatments (PReDICT) study and from whom plasma and serum samples were available. The NESDA-defined inflammatory index, a composite measure of interleukin-6 and C-reactive protein, was measured from pre-treatment plasma samples and a metabolomic profile was defined using serum samples analyzed on three metabolomics platforms targeting fatty acids and complex lipids, amino acids, acylcarnitines, and gut microbiome-derived metabolites among other metabolites of central metabolism. RESULTS: The IMD clinical dimension and the inflammatory index were positively correlated (r = 0.19, p = 0.019) after controlling for age, sex, and body mass index, whereas the Melancholic and Anxious distress dimensions were not, replicating the previous NESDA findings. The three symptom dimensions had distinct metabolomic signatures using both univariate and set enrichment statistics. IMD severity correlated mainly with gut-derived metabolites and a few acylcarnitines and long chain saturated free fatty acids. Melancholia severity was significantly correlated with several phosphatidylcholines, primarily the ether-linked variety, lysophosphatidylcholines, as well as several amino acids. Anxious distress severity correlated with several medium and long chain free fatty acids, both saturated and polyunsaturated ones, sphingomyelins, as well as several amino acids and bile acids. CONCLUSION: The IMD dimension of depression appears reliably associated with markers of inflammation. Metabolomics provides powerful tools to inform about depression heterogeneity and molecular mechanisms related to clinical dimensions in MDD, which include a link to gut microbiome and lipids implicated in membrane structure and function.

The landscape of metabolic brain alterations in Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) is accompanied by metabolic alterations both in the periphery and the central nervous system. However, so far, a global view of AD-associated metabolic changes in the brain has been missing. METHODS: We metabolically profiled 500 samples from the dorsolateral prefrontal cortex. Metabolite levels were correlated with eight clinical parameters, covering both late-life cognitive performance and AD neuropathology measures. RESULTS: We observed widespread metabolic dysregulation associated with AD, spanning 298 metabolites from various AD-relevant pathways. These included alterations to bioenergetics, cholesterol metabolism, neuroinflammation, and metabolic consequences of neurotransmitter ratio imbalances. Our findings further suggest impaired osmoregulation as a potential pathomechanism in AD. Finally, inspecting the interplay of proteinopathies provided evidence that metabolic associations were largely driven by tau pathology rather than amyloid beta pathology. DISCUSSION: This work provides a comprehensive reference map of metabolic brain changes in AD that lays the foundation for future mechanistic follow-up studies.

Integrative metabolomics-genomics approach reveals key metabolic pathways and regulators of Alzheimer's disease.

Metabolites, the biochemical products of the cellular process, can be used to measure alterations in biochemical pathways related to the pathogenesis of Alzheimer's disease (AD). However, the relationships between systemic abnormalities in metabolism and the pathogenesis of AD are poorly understood. In this study, we aim to identify AD-specific metabolomic changes and their potential upstream genetic and transcriptional regulators through an integrative systems biology framework for analyzing genetic, transcriptomic, metabolomic, and proteomic data in AD. Metabolite co-expression network analysis of the blood metabolomic data in the Alzheimer's Disease Neuroimaging Initiative (ADNI) shows short-chain acylcarnitines/amino acids and medium/long-chain acylcarnitines are most associated with AD clinical outcomes, including episodic memory scores and disease severity. Integration of the gene expression data in both the blood from the ADNI and the brain from the Accelerating Medicines Partnership Alzheimer's Disease (AMP-AD) program reveals ABCA1 and CPT1A are involved in the regulation of acylcarnitines and amino acids in AD. Gene co-expression network analysis of the AMP-AD brain RNA-seq data suggests the CPT1A- and ABCA1-centered subnetworks are associated with neuronal system and immune response, respectively. Increased ABCA1 gene expression and adiponectin protein, a regulator of ABCA1, correspond to decreased short-chain acylcarnitines and amines in AD in the ADNI. In summary, our integrated analysis of large-scale multiomics data in AD systematically identifies novel metabolites and their potential regulators in AD and the findings pave a way for not only developing sensitive and specific diagnostic biomarkers for AD but also identifying novel molecular mechanisms of AD pathogenesis.

APOE ε2 resilience for Alzheimer's disease is mediated by plasma lipid species: Analysis of three independent cohort studies.

INTRODUCTION: The apolipoprotein E (APOE) genotype is the strongest genetic risk factor for late-onset Alzheimer's disease. However, its effect on lipid metabolic pathways, and their mediating effect on disease risk, is poorly understood. METHODS: We performed lipidomic analysis on three independent cohorts (the Australian Imaging, Biomarkers and Lifestyle [AIBL] flagship study, n = 1087; the Alzheimer's Disease Neuroimaging Initiative [ADNI] 1 study, n = 819; and the Busselton Health Study [BHS], n = 4384), and we defined associations between APOE ε2 and ε4 and 569 plasma/serum lipid species. Mediation analysis defined the proportion of the treatment effect of the APOE genotype mediated by plasma/serum lipid species. RESULTS: A total of 237 and 104 lipid species were associated with APOE ε2 and ε4, respectively. Of these 68 (ε2) and 24 (ε4) were associated with prevalent Alzheimer's disease. Individual lipid species or lipidomic models of APOE genotypes mediated up to 30% and 10% of APOE ε2 and ε4 treatment effect, respectively. DISCUSSION: Plasma lipid species mediate the treatment effect of APOE genotypes on Alzheimer's disease and as such represent a potential therapeutic target.

RubiN - continuous care in regional networks: a study protocol for a prospective controlled trial.

BACKGROUND: The health care situation of geriatric patients is often multifaceted, complex and often overlaps with social living conditions. Due to the lack of cross-sectoral and interprofessional health care geriatric patients often, receive insufficient care. Only a holistic view enables a comprehensive evaluation of the complex health risks, but also the potential to preserve the health of geriatric patients. The implementation of cross-sectoral, multi-professional case management could reduce the gaps in care, improve the autonomy of the geriatric patients in their own homes, and allow them to retain it as long as possible. The "RubiN" project examines the effects of multi-professional, cross-sectoral and assessment-based case management on the quality of the care of geriatric patients. The results of the study aim to show whether geriatric patients receive better care using case management than patients who receive standard health care. In addition, data on the effects of case management on practices of general practitioners (GP), the satisfaction with the care concept amongst the case managers, patients and relatives will be collected. Furthermore, a health economic analysis will be carried out. METHODS: The project is designed as a prospective controlled study and compares geriatric patients from practice networks in different regions in Germany. Inclusion criteria are: Age ≥ 70 years and care requirements from two different care complexes (identified with the screening instrument 'Angelina'-questionnaire). The intervention is the use of a geriatric case management, where health care is organised based on patient-specific care requirements. Five practice networks of physicians will implement the intervention (n = 3200 patients) and three practice networks will serve as the control group (n = 1200 patients). The primary endpoint is the ability to manage activities of daily living, measured using the Barthel Index. The patients in the intervention group receive geriatric case management and the patients in the control networks receive standard care ("care as usual"). The analysis of the primary data, which is pseudonymised, occurs according to the intention-to-treat principle. For this purpose, the endpoints will be analysed using a group comparison after 12 months. For the health economic analysis, secondary data from the statutory health insurance providers will be included in the analysis, in addition to the primary data. Data for the analysis of the effects the concept has on the GP practices as well as on the satisfaction of the project participants will be collected with questionnaires and interviews with experts. DISCUSSION: The implementation of cross-sectoral and interdisciplinary geriatric case management has been a topic of discussion for years, whereby positive effects have already been-shown. This planned study will be the first evaluation of the effect of case management for geriatric patients with a very large sample. In addition, the effects of case management on the GP practices and also on the relatives of the geriatric patients will be shown. It is intended that the study results pave the way for a widespread implementation of this concept. TRIAL REGISTRATION: German Clinical Trials Register, ID: DRKS00016642 . Registered on 29 October 2019 - Retrospectively registered.

Circulating ethanolamine plasmalogen indices in Alzheimer's disease: Relation to diagnosis, cognition, and CSF tau.

INTRODUCTION: Altered lipid metabolism is implicated in Alzheimer's disease (AD), but the mechanisms remain obscure. Aging-related declines in circulating plasmalogens containing omega-3 fatty acids may increase AD risk by reducing plasmalogen availability. METHODS: We measured four ethanolamine plasmalogens (PlsEtns) and four closely related phosphatidylethanolamines (PtdEtns) from the Alzheimer's Disease Neuroimaging Initiative (ADNI; n = 1547 serum) and University of Pennsylvania (UPenn; n = 112 plasma) cohorts, and derived indices reflecting PlsEtn and PtdEtn metabolism: PL-PX (PlsEtns), PL/PE (PlsEtn/PtdEtn ratios), and PBV (plasmalogen biosynthesis value; a composite index). We tested associations with baseline diagnosis, cognition, and cerebrospinal fluid (CSF) AD biomarkers. RESULTS: Results revealed statistically significant negative relationships in ADNI between AD versus CN with PL-PX (P = 0.007) and PBV (P = 0.005), late mild cognitive impairment (LMCI) versus cognitively normal (CN) with PL-PX (P = 2.89 × 10-5 ) and PBV (P = 1.99 × 10-4 ), and AD versus LMCI with PL/PE (P = 1.85 × 10-4 ). In the UPenn cohort, AD versus CN diagnosis associated negatively with PL/PE (P = 0.0191) and PBV (P = 0.0296). In ADNI, cognition was negatively associated with plasmalogen indices, including Alzheimer's Disease Assessment Scale 13-item cognitive subscale (ADAS-Cog13; PL-PX: P = 3.24 × 10-6 ; PBV: P = 6.92 × 10-5 ) and Mini-Mental State Examination (MMSE; PL-PX: P = 1.28 × 10-9 ; PBV: P = 6.50 × 10-9 ). In the UPenn cohort, there was a trend toward a similar relationship of MMSE with PL/PE (P = 0.0949). In ADNI, CSF total-tau was negatively associated with PL-PX (P = 5.55 × 10-6 ) and PBV (P = 7.77 × 10-6 ). Additionally, CSF t-tau/Aß1-42 ratio was negatively associated with these same indices (PL-PX, P = 2.73 × 10-6 ; PBV, P = 4.39 × 10-6 ). In the UPenn cohort, PL/PE was negatively associated with CSF total-tau (P = 0.031) and t-tau/Aß1-42 (P = 0.021). CSF Aß1-42 was not significantly associated with any of these indices in either cohort. DISCUSSION: These data extend previous studies by showing an association of decreased plasmalogen indices with AD, mild cognitive impairment (MCI), cognition, and CSF tau. Future studies are needed to better define mechanistic relationships, and to test the effects of interventions designed to replete serum plasmalogens.

A one stop shop for cost-effectiveness evidence? Recommendations for improving Disease Control Priorities.

Setting out a health benefits package (HBP) of interventions to be prioritised for funding is an important step towards achieving universal health coverage in low and middle income countries. The 3rd version of the Disease Control Priorities (DCP3) database, and other similar databases, aim to establishing a single point of reference ("one stop shop") for cost effectiveness evidence to inform HBP design and other policy making. We reflect upon our experiences in using DCP3 for HBP design and offer suggestions for improving the future reporting of cost-effectiveness evidence. We appraise DCP3 based on generalisability, level of detail, and accessibility. We find that DCP and similar initiatives should be commended for the systematic assessment of a vast array of cost-effectiveness studies-the magnitude of such an endeavour is impressive in its own right. However, there are flaws. In future, providing disaggregated estimates of costs and effects, quantifying uncertainty, and systematically assessing the context in which estimates apply would make this evidence more useful for decision makers.

Altered bile acid profile in mild cognitive impairment and Alzheimer's disease: Relationship to neuroimaging and CSF biomarkers.

INTRODUCTION: Bile acids (BAs) are the end products of cholesterol metabolism produced by human and gut microbiome co-metabolism. Recent evidence suggests gut microbiota influence pathological features of Alzheimer's disease (AD) including neuroinflammation and amyloid-ß deposition. METHOD: Serum levels of 20 primary and secondary BA metabolites from the AD Neuroimaging Initiative (n = 1562) were measured using targeted metabolomic profiling. We assessed the association of BAs with the "A/T/N" (amyloid, tau, and neurodegeneration) biomarkers for AD: cerebrospinal fluid (CSF) biomarkers, atrophy (magnetic resonance imaging), and brain glucose metabolism ([18F]FDG PET). RESULTS: Of 23 BAs and relevant calculated ratios after quality control procedures, three BA signatures were associated with CSF Aß1-42 ("A") and three with CSF p-tau181 ("T") (corrected P < .05). Furthermore, three, twelve, and fourteen BA signatures were associated with CSF t-tau, glucose metabolism, and atrophy ("N"), respectively (corrected P < .05). DISCUSSION: This is the first study to show serum-based BA metabolites are associated with "A/T/N" AD biomarkers, providing further support for a role of BA pathways in AD pathophysiology. Prospective clinical observations and validation in model systems are needed to assess causality and specific mechanisms underlying this association.

Altered bile acid profile associates with cognitive impairment in Alzheimer's disease-An emerging role for gut microbiome.

INTRODUCTION: Increasing evidence suggests a role for the gut microbiome in central nervous system disorders and a specific role for the gut-brain axis in neurodegeneration. Bile acids (BAs), products of cholesterol metabolism and clearance, are produced in the liver and are further metabolized by gut bacteria. They have major regulatory and signaling functions and seem dysregulated in Alzheimer's disease (AD). METHODS: Serum levels of 15 primary and secondary BAs and their conjugated forms were measured in 1464 subjects including 370 cognitively normal older adults, 284 with early mild cognitive impairment, 505 with late mild cognitive impairment, and 305 AD cases enrolled in the AD Neuroimaging Initiative. We assessed associations of BA profiles including selected ratios with diagnosis, cognition, and AD-related genetic variants, adjusting for confounders and multiple testing. RESULTS: In AD compared to cognitively normal older adults, we observed significantly lower serum concentrations of a primary BA (cholic acid [CA]) and increased levels of the bacterially produced, secondary BA, deoxycholic acid, and its glycine and taurine conjugated forms. An increased ratio of deoxycholic acid:CA, which reflects 7α-dehydroxylation of CA by gut bacteria, strongly associated with cognitive decline, a finding replicated in serum and brain samples in the Rush Religious Orders and Memory and Aging Project. Several genetic variants in immune response-related genes implicated in AD showed associations with BA profiles. DISCUSSION: We report for the first time an association between altered BA profile, genetic variants implicated in AD, and cognitive changes in disease using a large multicenter study. These findings warrant further investigation of gut dysbiosis and possible role of gut-liver-brain axis in the pathogenesis of AD.

Brain and blood metabolite signatures of pathology and progression in Alzheimer disease: A targeted metabolomics study.

BACKGROUND: The metabolic basis of Alzheimer disease (AD) is poorly understood, and the relationships between systemic abnormalities in metabolism and AD pathogenesis are unclear. Understanding how global perturbations in metabolism are related to severity of AD neuropathology and the eventual expression of AD symptoms in at-risk individuals is critical to developing effective disease-modifying treatments. In this study, we undertook parallel metabolomics analyses in both the brain and blood to identify systemic correlates of neuropathology and their associations with prodromal and preclinical measures of AD progression. METHODS AND FINDINGS: Quantitative and targeted metabolomics (Biocrates AbsoluteIDQ [identification and quantification] p180) assays were performed on brain tissue samples from the autopsy cohort of the Baltimore Longitudinal Study of Aging (BLSA) (N = 44, mean age = 81.33, % female = 36.36) from AD (N = 15), control (CN; N = 14), and "asymptomatic Alzheimer's disease" (ASYMAD, i.e., individuals with significant AD pathology but no cognitive impairment during life; N = 15) participants. Using machine-learning methods, we identified a panel of 26 metabolites from two main classes-sphingolipids and glycerophospholipids-that discriminated AD and CN samples with accuracy, sensitivity, and specificity of 83.33%, 86.67%, and 80%, respectively. We then assayed these 26 metabolites in serum samples from two well-characterized longitudinal cohorts representing prodromal (Alzheimer's Disease Neuroimaging Initiative [ADNI], N = 767, mean age = 75.19, % female = 42.63) and preclinical (BLSA) (N = 207, mean age = 78.68, % female = 42.63) AD, in which we tested their associations with magnetic resonance imaging (MRI) measures of AD-related brain atrophy, cerebrospinal fluid (CSF) biomarkers of AD pathology, risk of conversion to incident AD, and trajectories of cognitive performance. We developed an integrated blood and brain endophenotype score that summarized the relative importance of each metabolite to severity of AD pathology and disease progression (Endophenotype Association Score in Early Alzheimer's Disease [EASE-AD]). Finally, we mapped the main metabolite classes emerging from our analyses to key biological pathways implicated in AD pathogenesis. We found that distinct sphingolipid species including sphingomyelin (SM) with acyl residue sums C16:0, C18:1, and C16:1 (SM C16:0, SM C18:1, SM C16:1) and hydroxysphingomyelin with acyl residue sum C14:1 (SM (OH) C14:1) were consistently associated with severity of AD pathology at autopsy and AD progression across prodromal and preclinical stages. Higher log-transformed blood concentrations of all four sphingolipids in cognitively normal individuals were significantly associated with increased risk of future conversion to incident AD: SM C16:0 (hazard ratio [HR] = 4.430, 95% confidence interval [CI] = 1.703-11.520, p = 0.002), SM C16:1 (HR = 3.455, 95% CI = 1.516-7.873, p = 0.003), SM (OH) C14:1 (HR = 3.539, 95% CI = 1.373-9.122, p = 0.009), and SM C18:1 (HR = 2.255, 95% CI = 1.047-4.855, p = 0.038). The sphingolipid species identified map to several biologically relevant pathways implicated in AD, including tau phosphorylation, amyloid-ß (Aß) metabolism, calcium homeostasis, acetylcholine biosynthesis, and apoptosis. Our study has limitations: the relatively small number of brain tissue samples may have limited our power to detect significant associations, control for heterogeneity between groups, and replicate our findings in independent, autopsy-derived brain samples. CONCLUSIONS: We present a novel framework to identify biologically relevant brain and blood metabolites associated with disease pathology and progression during the prodromal and preclinical stages of AD. Our results show that perturbations in sphingolipid metabolism are consistently associated with endophenotypes across preclinical and prodromal AD, as well as with AD pathology at autopsy. Sphingolipids may be biologically relevant biomarkers for the early detection of AD, and correcting perturbations in sphingolipid metabolism may be a plausible and novel therapeutic strategy in AD.

Personalized Mammography Screening and Screening Adherence-A Simulation and Economic Evaluation.

OBJECTIVE: Personalized breast cancer screening has so far been economically evaluated under the assumption of full screening adherence. This is the first study to evaluate the effects of nonadherence on the evaluation and selection of personalized screening strategies. METHODS: Different adherence scenarios were established on the basis of findings from the literature. A Markov microsimulation model was adapted to evaluate the effects of these adherence scenarios on three different personalized strategies. RESULTS: First, three adherence scenarios describing the relationship between risk and adherence were identified: 1) a positive association between risk and screening adherence, 2) a negative association, or 3) a curvilinear relationship. Second, these three adherence scenarios were evaluated in three personalized strategies. Our results show that it is more the absolute adherence rate than the nature of the risk-adherence relationship that is important to determine which strategy is the most cost-effective. Furthermore, probabilistic sensitivity analyses showed that there are risk-stratified screening strategies that are more cost-effective than routine screening if the willingness-to-pay threshold for screening is below US $60,000. CONCLUSIONS: Our results show that "nonadherence" affects the relative performance of screening strategies. Thus, it is necessary to include the true adherence level to evaluate personalized screening strategies and to select the best strategy.

Genome-Wide Association Study with Targeted and Non-targeted NMR Metabolomics Identifies 15 Novel Loci of Urinary Human Metabolic Individuality.

Genome-wide association studies with metabolic traits (mGWAS) uncovered many genetic variants that influence human metabolism. These genetically influenced metabotypes (GIMs) contribute to our metabolic individuality, our capacity to respond to environmental challenges, and our susceptibility to specific diseases. While metabolic homeostasis in blood is a well investigated topic in large mGWAS with over 150 known loci, metabolic detoxification through urinary excretion has only been addressed by few small mGWAS with only 11 associated loci so far. Here we report the largest mGWAS to date, combining targeted and non-targeted 1H NMR analysis of urine samples from 3,861 participants of the SHIP-0 cohort and 1,691 subjects of the KORA F4 cohort. We identified and replicated 22 loci with significant associations with urinary traits, 15 of which are new (HIBCH, CPS1, AGXT, XYLB, TKT, ETNPPL, SLC6A19, DMGDH, SLC36A2, GLDC, SLC6A13, ACSM3, SLC5A11, PNMT, SLC13A3). Two-thirds of the urinary loci also have a metabolite association in blood. For all but one of the 6 loci where significant associations target the same metabolite in blood and urine, the genetic effects have the same direction in both fluids. In contrast, for the SLC5A11 locus, we found increased levels of myo-inositol in urine whereas mGWAS in blood reported decreased levels for the same genetic variant. This might indicate less effective re-absorption of myo-inositol in the kidneys of carriers. In summary, our study more than doubles the number of known loci that influence urinary phenotypes. It thus allows novel insights into the relationship between blood homeostasis and its regulation through excretion. The newly discovered loci also include variants previously linked to chronic kidney disease (CPS1, SLC6A13), pulmonary hypertension (CPS1), and ischemic stroke (XYLB). By establishing connections from gene to disease via metabolic traits our results provide novel hypotheses about molecular mechanisms involved in the etiology of diseases.

Addressing the double-burden of diabetes and tuberculosis: lessons from Kyrgyzstan.

BACKGROUND: The incidence of diabetes and tuberculosis co-morbidity is rising, yet little work has been done to understand potential implications for health systems, healthcare providers and individuals. Kyrgyzstan is a priority country for tuberculosis control and has a 5% prevalence of diabetes in adults, with many health system challenges for both conditions. METHODS: Patient exit interviews collected data on demographic and socio-economic characteristics, health spending and care seeking for people with diabetes, tuberculosis and both diabetes and tuberculosis. Qualitative data were collected through semi-structured interviews with healthcare workers involved in diabetes and tuberculosis care, to understand delivery of care and how providers view effectiveness of care. RESULTS: The experience of co-affected individuals within the health system is different than those just with tuberculosis or diabetes. Co-affected patients do not receive more care and also have different care for their tuberculosis than people with only tuberculosis. Very high levels of catastrophic spending are found among all groups despite these two conditions being included in the Kyrgyz state benefit package especially for medicines. CONCLUSIONS: This study highlights that different patterns of service provision by disease group are found. Although Kyrgyzstan has often been cited as an example in terms of health reforms and developing Primary Health Care, this study highlights the challenge of managing conditions that are viewed as "too complicated" for non-specialists and the impact this has on costs and management of individuals.

Simulation modeling for stratified breast cancer screening - a systematic review of cost and quality of life assumptions.

BACKGROUND: The economic evaluation of stratified breast cancer screening gains momentum, but produces also very diverse results. Systematic reviews so far focused on modeling techniques and epidemiologic assumptions. However, cost and utility parameters received only little attention. This systematic review assesses simulation models for stratified breast cancer screening based on their cost and utility parameters in each phase of breast cancer screening and care. METHODS: A literature review was conducted to compare economic evaluations with simulation models of personalized breast cancer screening. Study quality was assessed using reporting guidelines. Cost and utility inputs were extracted, standardized and structured using a care delivery framework. Studies were then clustered according to their study aim and parameters were compared within the clusters. RESULTS: Eighteen studies were identified within three study clusters. Reporting quality was very diverse in all three clusters. Only two studies in cluster 1, four studies in cluster 2 and one study in cluster 3 scored high in the quality appraisal. In addition to the quality appraisal, this review assessed if the simulation models were consistent in integrating all relevant phases of care, if utility parameters were consistent and methodological sound and if cost were compatible and consistent in the actual parameters used for screening, diagnostic work up and treatment. Of 18 studies, only three studies did not show signs of potential bias. CONCLUSION: This systematic review shows that a closer look into the cost and utility parameter can help to identify potential bias. Future simulation models should focus on integrating all relevant phases of care, using methodologically sound utility parameters and avoiding inconsistent cost parameters.

Metabolic network failures in Alzheimer's disease: A biochemical road map.

INTRODUCTION: The Alzheimer's Disease Research Summits of 2012 and 2015 incorporated experts from academia, industry, and nonprofit organizations to develop new research directions to transform our understanding of Alzheimer's disease (AD) and propel the development of critically needed therapies. In response to their recommendations, big data at multiple levels are being generated and integrated to study network failures in disease. We used metabolomics as a global biochemical approach to identify peripheral metabolic changes in AD patients and correlate them to cerebrospinal fluid pathology markers, imaging features, and cognitive performance. METHODS: Fasting serum samples from the Alzheimer's Disease Neuroimaging Initiative (199 control, 356 mild cognitive impairment, and 175 AD participants) were analyzed using the AbsoluteIDQ-p180 kit. Performance was validated in blinded replicates, and values were medication adjusted. RESULTS: Multivariable-adjusted analyses showed that sphingomyelins and ether-containing phosphatidylcholines were altered in preclinical biomarker-defined AD stages, whereas acylcarnitines and several amines, including the branched-chain amino acid valine and α-aminoadipic acid, changed in symptomatic stages. Several of the analytes showed consistent associations in the Rotterdam, Erasmus Rucphen Family, and Indiana Memory and Aging Studies. Partial correlation networks constructed for Aß1-42, tau, imaging, and cognitive changes provided initial biochemical insights for disease-related processes. Coexpression networks interconnected key metabolic effectors of disease. DISCUSSION: Metabolomics identified key disease-related metabolic changes and disease-progression-related changes. Defining metabolic changes during AD disease trajectory and its relationship to clinical phenotypes provides a powerful roadmap for drug and biomarker discovery.