![]() Sixteen of the 100 models had a better c-statistic compared to an age-only model and 15 metabolites were selected at least once in all 16 models with glucose present in all models. Risk scores reflecting the frequency with which predictors appeared in the selected models were constructed, and their predictive accuracy was examined using Royston’s R ², Akaike’s information criterion, sensitivity, specificity, C-statistic and calibration. Elastic net penalized Cox regression with 100 repetitions of nested cross-validation was used to select models that improved prediction accuracy for incident dementia compared to an age-only model. Participants were followed for a median 21.0 (IQR 20.4, 21.7) years for clinically-diagnosed dementia ( N =329). We examined the role of midlife serum metabolites using a machine learning approach and determined whether the selected metabolites improved prediction accuracy beyond the effect of age.įive thousand three hundred seventy-four participants from the Whitehall II study, mean age 55.8 (standard deviation (SD) 6.0) years in 1997–1999 when 233 metabolites were quantified using nuclear magnetic resonance metabolomics. SAA, Serum Amyloid A SDA, Symmetric Dimethylarginine.Īge is the strongest risk factor for dementia and there is considerable interest in identifying scalable, blood-based biomarkers in predicting dementia. RYGB, exercise, and diet restore HDL functionality and alter composition to varying degrees. Metabolic interventions have been shown to improve HDL functionality. Dysfunctional HDLs also present an altered miRNA profile, with increase in pro-inflammatory miRNA 24. SAA and SDA are become associated to HDL. The lipidome and proteome of HDLs are altered, with increased TG and decreased PL. Throughout the pathogenesis of cardiovascular disease, HDLs becomes progressively more dysfunctional. Healthy HDLs have a high PL content and are highly associated to beneficial molecules, such as S1P and PON-1 enzyme exerting a beneficial role on ECs, or anti-atherosclerotic miRNA 223. (B) Diagram detailing the various actions of HDLs in health and disease. (3) Catabolism: finally, after a roughly 4 to 5 day lifecycle, HDLs are permanently catabolized either in the liver via the ecto-F 1 -ATPase or through complete delipidation by SR-B1 in the kidney and urinary excretion. (2) Function: HDLs main function are to efflux cholesterol and other lipids from peripheral tissues (such as the cardio-vascular system) and transport them either to (a) the liver for disposal, (b) steroidogenic tissues to support hormone production or (c) exchange lipids with apoB-containing particles. Further lipidation results in mature HDL formation, which can in-turn become pre-ß HDL via the catabolic action of endothelial (EL) and hepatic (HL) lipases. (1) Synthesis: ApoA1 is synthesized in the liver and the gut, where it can be gradually lipidated on-site or by the adipose tissue to produce pre-ß HDLs. Diagram detailing the three key stages of the HDL lifecycle.
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