We investigated relations between amyloid-β (Aβ) status, apolipoprotein E (APOE) ε4, and cognition, with cerebrospinal fluid markers of neurogranin (Ng), neurofilament light (NFL), YKL-40, and total ...tau (T-tau).
We included 770 individuals with normal cognition, mild cognitive impairment, and Alzheimer's disease (AD)-type dementia from the EMIF-AD Multimodal Biomarker Discovery study. We tested the association of Ng, NFL, YKL-40, and T-tau with Aβ status (Aβ− vs. Aβ+), clinical diagnosis APOE ε4 carriership, baseline cognition, and change in cognition.
Ng and T-tau distinguished between Aβ+ from Aβ− individuals in each clinical group, whereas NFL and YKL-40 were associated with Aβ+ in nondemented individuals only. APOE ε4 carriership did not influence NFL, Ng, and YKL-40 in Aβ+ individuals. NFL was the best predictor of cognitive decline in Aβ+ individuals across the cognitive spectrum.
Axonal degeneration, synaptic dysfunction, astroglial activation, and altered tau metabolism are involved already in preclinical AD. NFL may be a useful prognostic marker.
Abstract 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 Aβ1–42 , 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.
A specific, sensitive and essentially non-invasive assay to diagnose and monitor Alzheimer's disease (AD) would be valuable to both clinicians and medical researchers. The aim of this study was to ...perform a metabonomic statistical analysis on plasma fingerprints. Objectives were to investigate novel biomarkers indicative of AD, to consider the role of bile acids as AD biomarkers and to consider whether mild cognitive impairment (MCI) is a separate disease from AD. Samples were analysed by ultraperformance liquid chromatography-MS and resulting data sets were interpreted using soft-independent modelling of class analogy statistical analysis methods. PCA models did not show any grouping of subjects by disease state. Partial least-squares discriminant analysis (PLS-DS) models yielded class separation for AD. However, as with earlier studies, model validation revealed a predictive power of Q²<0.5 and indicating their unsuitability for predicting disease state. Three bile acids were extracted from the data and quantified, up-regulation was observed for MCI and AD patients. PLS-DA did not support MCI being considered as a separate disease from AD with MCI patient metabolic profiles being significantly closer to AD patients than controls. This study suggested that further investigation into the lipid fraction of the metabolome may yield useful biomarkers for AD and metabolomic profiles could be used to predict disease state in a clinical setting.
Type 2 diabetes is a multifactorial disease with multiple underlying aetiologies. To address this heterogeneity, investigators of a previous study clustered people with diabetes according to five ...diabetes subtypes. The aim of the current study is to investigate the etiology of these clusters by comparing their molecular signatures. In three independent cohorts, in total 15,940 individuals were clustered based on five clinical characteristics. In a subset, genetic (
= 12,828), metabolomic (
= 2,945), lipidomic (
= 2,593), and proteomic (
= 1,170) data were obtained in plasma. For each data type, each cluster was compared with the other four clusters as the reference. The insulin-resistant cluster showed the most distinct molecular signature, with higher branched-chain amino acid, diacylglycerol, and triacylglycerol levels and aberrant protein levels in plasma were enriched for proteins in the intracellular PI3K/Akt pathway. The obese cluster showed higher levels of cytokines. The mild diabetes cluster with high HDL showed the most beneficial molecular profile with effects opposite of those seen in the insulin-resistant cluster. This study shows that clustering people with type 2 diabetes can identify underlying molecular mechanisms related to pancreatic islets, liver, and adipose tissue metabolism. This provides novel biological insights into the diverse aetiological processes that would not be evident when type 2 diabetes is viewed as a homogeneous disease.
Introduction
This study employed an integrative system and causal inference approach to explore molecular signatures in blood and CSF, the amyloid/tau/neurodegeneration AT(N) framework, mild ...cognitive impairment (MCI) conversion to Alzheimer's disease (AD), and genetic risk for AD.
Methods
Using the European Medical Information Framework (EMIF)‐AD cohort, we measured 696 proteins in cerebrospinal fluid (n = 371), 4001 proteins in plasma (n = 972), 611 metabolites in plasma (n = 696), and genotyped whole‐blood (7,778,465 autosomal single nucleotide epolymorphisms, n = 936). We investigated associations: molecular modules to AT(N), module hubs with AD Polygenic Risk scores and APOE4 genotypes, molecular hubs to MCI conversion and probed for causality with AD using Mendelian randomization (MR).
Results
AT(N) framework associated with protein and lipid hubs. In plasma, Proprotein Convertase Subtilisin/Kexin Type 7 showed evidence for causal associations with AD. AD was causally associated with Reticulocalbin 2 and sphingomyelins, an association driven by the APOE isoform.
Discussion
This study reveals multi‐omics networks associated with AT(N) and causal AD molecular candidates.
There is growing evidence that Alzheimer disease (AD) is a pervasive metabolic disorder with dysregulation in multiple biochemical pathways underlying its pathogenesis. Understanding how ...perturbations in metabolism are related to AD is critical to identifying novel targets for disease-modifying therapies. In this study, we test whether AD pathogenesis is associated with dysregulation in brain transmethylation and polyamine pathways.
We first performed targeted and quantitative metabolomics assays using capillary electrophoresis-mass spectrometry (CE-MS) on brain samples from three groups in the Baltimore Longitudinal Study of Aging (BLSA) (AD: n = 17; Asymptomatic AD ASY: n = 13; Control CN: n = 13) (overall 37.2% female; mean age at death 86.118 ± 9.842 years) in regions both vulnerable and resistant to AD pathology. Using linear mixed-effects models within two primary brain regions (inferior temporal gyrus ITG and middle frontal gyrus MFG), we tested associations between brain tissue concentrations of 26 metabolites and the following primary outcomes: group differences, Consortium to Establish a Registry for Alzheimer's Disease (CERAD) (neuritic plaque burden), and Braak (neurofibrillary pathology) scores. We found significant alterations in concentrations of metabolites in AD relative to CN samples, as well as associations with severity of both CERAD and Braak, mainly in the ITG. These metabolites represented biochemical reactions in the (1) methionine cycle (choline: lower in AD, p = 0.003; S-adenosyl methionine: higher in AD, p = 0.005); (2) transsulfuration and glutathione synthesis (cysteine: higher in AD, p < 0.001; reduced glutathione GSH: higher in AD, p < 0.001); (3) polyamine synthesis/catabolism (spermidine: higher in AD, p = 0.004); (4) urea cycle (N-acetyl glutamate: lower in AD, p < 0.001); (5) glutamate-aspartate metabolism (N-acetyl aspartate: lower in AD, p = 0.002); and (6) neurotransmitter metabolism (gamma-amino-butyric acid: lower in AD, p < 0.001). Utilizing three Gene Expression Omnibus (GEO) datasets, we then examined mRNA expression levels of 71 genes encoding enzymes regulating key reactions within these pathways in the entorhinal cortex (ERC; AD: n = 25; CN: n = 52) and hippocampus (AD: n = 29; CN: n = 56). Complementing our metabolomics results, our transcriptomics analyses also revealed significant alterations in gene expression levels of key enzymatic regulators of biochemical reactions linked to transmethylation and polyamine metabolism. Our study has limitations: our metabolomics assays measured only a small proportion of all metabolites participating in the pathways we examined. Our study is also cross-sectional, limiting our ability to directly test how AD progression may impact changes in metabolite concentrations or differential-gene expression. Additionally, the relatively small number of brain tissue samples may have limited our power to detect alterations in all pathway-specific metabolites and their genetic regulators.
In this study, we observed broad dysregulation of transmethylation and polyamine synthesis/catabolism, including abnormalities in neurotransmitter signaling, urea cycle, aspartate-glutamate metabolism, and glutathione synthesis. Our results implicate alterations in cellular methylation potential and increased flux in the transmethylation pathways, increased demand on antioxidant defense mechanisms, perturbations in intermediate metabolism in the urea cycle and aspartate-glutamate pathways disrupting mitochondrial bioenergetics, increased polyamine biosynthesis and breakdown, as well as abnormalities in neurotransmitter metabolism that are related to AD.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Alzheimer’s disease (AD) is a progressive neurodegenerative disease which affects a growing number of people as the population ages worldwide. Alzheimer’s Disease International estimated that more ...than 100 million people will be living with dementia by 2050. At present there are no disease-modifying therapies and research has expanded to the −omic sciences with scientists aiming to get a holistic view of the disease using systems medicine. Metabolomics and Lipidomics give a snap-shot of the metabolism. As analyzing the brain in vivo is difficult, the metabolic information of the periphery has potential to unravel mechanisms that have not been considered, such as those that link the brain to the liver and the gut or other organs. With that in mind we have produced a mini-review, to record a number of studies in the field and the molecular pathways that have been flagged in animal and human models of AD. Human studies deal with cohorts in the order of the hundreds due to the difficulty of organizing AD studies, however it is possible that these first pilots point towards important mechanisms. The trend in these small studies is the involvement of many organs and pathways. Some findings, that have been reproduced, are ceramides being increased, phospholipids and neurotransmitters depleted and sterols being found depleted too. Initial findings point to an important role to lipid homeostasis in AD, this is not surprising as the brain’s main constituents are water and lipids.
La maladie d’Alzheimer est une maladie neurodégénérative progressive qui affecte un nombre croissant de personnes en raison du vieillissement de la population observé dans le monde entier. La fédération internationale d’associations Alzheimer’s disease International estime que plus de 100 millions de personnes vivront avec cette démence d’ici à 2050. Il n’existe actuellement aucun traitement de la maladie et la recherche s’est élargie aux sciences -omiques avec l’objectif scientifique d’obtenir une approche globale de la maladie en utilisant une médecine des systèmes. La métabolomique et la lipidomique donnent un aperçu du métabolisme. L’analyse du cerveau in vivo s’avérant difficile, l’information métabolique de la périphérie possède le potentiel de démêler des mécanismes qui n’ont pas été pris en compte, tels que ceux reliant le cerveau au foie et à l’intestin ou à d’autres organes. Dans cet esprit, nous proposons une mini-revue, afin de lister un certain nombre d’études relevant de ce champ et les voies moléculaires qui ont été signalées chez les modèles animaux et humains de la maladie d’Alzheimer. Les études humaines traitent des cohortes de quelque centaines d’individus en raison de la difficulté à organiser des études sur cette pathologie, mais il est possible que ces premiers pilotes pointent vers des mécanismes importants. La tendance dans ces petites études est l’implication de nombreux organes et voies. Certaines conclusions, qui ont été reproduites, indiquent que les céramides sont augmentées, les phospholipides et les neurotransmetteurs appauvris et les stérols également épuisés. Les premiers résultats indiquent un important rôle de l’homéostasie des lipides dans la maladie d’Alzheimer, ce qui ne semble guère surprenant puisque les principaux constituants du cerveau sont l’eau et les lipides.
Abstract Aims Heterogeneity in the rate of β ‐cell loss in newly diagnosed type 1 diabetes patients is poorly understood and creates a barrier to designing and interpreting disease‐modifying clinical ...trials. Integrative analyses of baseline multi‐omics data obtained after the diagnosis of type 1 diabetes may provide mechanistic insight into the diverse rates of disease progression after type 1 diabetes diagnosis. Methods We collected samples in a pan‐European consortium that enabled the concerted analysis of five different omics modalities in data from 97 newly diagnosed patients. In this study, we used Multi‐Omics Factor Analysis to identify molecular signatures correlating with post‐diagnosis decline in β ‐cell mass measured as fasting C‐peptide. Results Two molecular signatures were significantly correlated with fasting C‐peptide levels. One signature showed a correlation to neutrophil degranulation, cytokine signalling, lymphoid and non‐lymphoid cell interactions and G‐protein coupled receptor signalling events that were inversely associated with a rapid decline in β ‐cell function. The second signature was related to translation and viral infection was inversely associated with change in β ‐cell function. In addition, the immunomics data revealed a Natural Killer cell signature associated with rapid β ‐cell decline. Conclusions Features that differ between individuals with slow and rapid decline in β ‐cell mass could be valuable in staging and prediction of the rate of disease progression and thus enable smarter (shorter and smaller) trial designs for disease modifying therapies as well as offering biomarkers of therapeutic effect.
Background
Docosahexaenoic acid (DHA) is the main long chain omega‐3 polyunsaturated fatty acids in the brain and accounts for 30% to 40% of fatty acids in the grey matter of the human cortex. ...Although the influence of circulating DHA levels on memory function is widely researched, its association with brain volumes is under investigated and its association with spatial navigation is virtually unknown. This is despite the fact that spatial navigation deficits are a new cognitive fingerprint for symptomatic and asymptomatic AD, and that spatial navigation crucially relies on hippocampal and the entorhinal cortex integrity. Thus, we investigated the relationship between DHA levels and the major structural and cognitive markers of preclinical AD, namely hippocampal volume, entorhinal volume, and spatial navigation ability, across two independent non‐demented populations.
Method
Fifty‐three cognitively normal adults underwent volumetric magnetic resonance imaging, measurements of serum DHA (including serum lysophosphatidylcholine DHA) and APOE ε4 genotyping. Relative regional brain volumes were calculated and linear regression models were fitted to examine DHA associations with brain volume. After testing interactions between DHA and APOE ε4 on brain volume, we investigated whether DHA and APOE interact to predict spatial navigation performance on a novel virtual reality diagnostic test for AD in an independent population of APOE genotyped adults (n = 46). We hypothesized that higher DHA levels would be associated with preserved brain volume and better spatial navigation performance in APOE ε4 non‐carriers but not in APOE ε4 carriers.
Result
APOE genotype modulated serum free DHA associations with entorhinal cortex volume and hippocampal volume, both key nodes of the human spatial navigation network. Linear models showed that greater circulating DHA was associated with increased entorhinal cortex volume, but not hippocampal volume, in APOΕ ε4 non‐carriers. APOE also interacted with serum lysophosphatidylcholine DHA to predict hippocampal volume. Crucially, the APOE genotype modulated DHA associations with spatial navigation performance, showing that DHA was inversely associated with path integration in APOE ε4 carriers only.
Conclusion
Interventions aiming to increase DHA status to protect against cognitive decline must consider APOE ε4 carrier status.
Introduction
Despite increasing evidence of a role of rare genetic variation in the risk of Alzheimer's disease (AD), limited attention has been paid to its contribution to AD‐related biomarker ...traits indicative of AD‐relevant pathophysiological processes.
Methods
We performed whole‐exome gene‐based rare‐variant association studies (RVASs) of 17 AD‐related traits on whole‐exome sequencing (WES) data generated in the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF‐AD MBD) study (n = 450) and whole‐genome sequencing (WGS) data from ADNI (n = 808).
Results
Mutation screening revealed a novel probably pathogenic mutation (PSEN1 p.Leu232Phe). Gene‐based RVAS revealed the exome‐wide significant contribution of rare coding variation in RBKS and OR7A10 to cognitive performance and protection against left hippocampal atrophy, respectively.
Discussion
The identification of these novel gene–trait associations offers new perspectives into the role of rare coding variation in the distinct pathophysiological processes culminating in AD, which may lead to identification of novel therapeutic and diagnostic targets.
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