Nuclear magnetic resonance relaxometry is a uniquely practical and versatile implementation of NMR technology. Because it does not depend on chemical shift resolution, it can be performed using low-field compact instruments deployed in atypical settings. Early relaxometry studies of human blood were focused on developing a diagnostic test for cancer. Those efforts were misplaced, as the measurements were not specific to cancer. However, important lessons were learned about the factors that drive the water longitudinal (T1) and transverse (T2) relaxation times. One key factor is the overall distribution of proteins and lipoproteins. Plasma water T2 can detect shifts in the blood proteome resulting from inflammation, insulin resistance and dyslipidemia. In whole blood, T2 is sensitive to hemoglobin content and oxygenation, although the latter can be suppressed by manipulating the static and applied magnetic fields. Current applications of compact NMR relaxometry include blood tests for candidiasis, hemostasis, malaria and insulin resistance.
BackgroundMetabolic syndrome (MetS) is a highly prevalent condition that identifies individuals at risk for type 2 diabetes mellitus and atherosclerotic cardiovascular disease. Prevention of these diseases relies on early detection and intervention in order to preserve pancreatic β-cells and arterial wall integrity. Yet, the clinical criteria for MetS are insensitive to the early-stage insulin resistance, inflammation, cholesterol and clotting factor abnormalities that characterize the progression toward type 2 diabetes and atherosclerosis. Here we report the discovery and initial characterization of an atypical new biomarker that detects these early conditions with just one measurement.MethodsWater T2, measured in a few minutes using benchtop nuclear magnetic resonance relaxometry, is exquisitely sensitive to metabolic shifts in the blood proteome. In an observational cross-sectional study of 72 non-diabetic human subjects, the association of plasma and serum water T2 values with over 130 blood biomarkers was analyzed using bivariate, multivariate and logistic regression.ResultsPlasma and serum water T2 exhibited strong bivariate correlations with markers of insulin, lipids, inflammation, coagulation and electrolyte balance. After correcting for confounders, low water T2 values were independently and additively associated with fasting hyperinsulinemia, dyslipidemia and subclinical inflammation. Plasma water T2 exhibited 100% sensitivity and 87% specificity for detecting early insulin resistance in normoglycemic subjects, as defined by the McAuley Index. Sixteen normoglycemic subjects with early metabolic abnormalities (22% of the study population) were identified by low water T2 values. Thirteen of the 16 did not meet the harmonized clinical criteria for metabolic syndrome and would have been missed by conventional screening for diabetes risk. Low water T2 values were associated with increases in the mean concentrations of 6 of the 16 most abundant acute phase proteins and lipoproteins in plasma.ConclusionsWater T2 detects a constellation of early abnormalities associated with metabolic syndrome, providing a global view of an individual’s metabolic health. It circumvents the pitfalls associated with fasting glucose and hemoglobin A1c and the limitations of the current clinical criteria for metabolic syndrome. Water T2 shows promise as an early, global and practical screening tool for the identification of individuals at risk for diabetes and atherosclerosis.Electronic supplementary materialThe online version of this article (10.1186/s12967-017-1359-5) contains supplementary material, which is available to authorized users.
The functional properties of lipid-rich assemblies such as serum lipoproteins, cell membranes, and intracellular lipid droplets are modulated by the fluidity of the hydrocarbon chain environment. Existing methods for monitoring hydrocarbon chain fluidity include fluorescence, electron spin resonance, and nuclear magnetic resonance (NMR) spectroscopy; each possesses advantages and limitations. Here we introduce a new approach based on benchtop time-domain (1)H NMR relaxometry (TD-NMR). Unlike conventional NMR spectroscopy, TD-NMR does not rely on the chemical shift resolution made possible by homogeneous, high-field magnets and Fourier transforms. Rather, it focuses on a multiexponential analysis of the time decay signal. In this study, we investigated a series of single-phase fatty acid oils, which allowed us to correlate (1)H spin-spin relaxation time constants (T2) with experimental measures of sample fluidity, as obtained using a viscometer. Remarkably, benchtop TD-NMR at 40 MHz was able to resolve two to four T2 components in biologically relevant fatty acids, assigned to nanometer-scale domains in different segments of the hydrocarbon chain. The T2 values for each domain were exquisitely sensitive to hydrocarbon chain structure; the largest values were observed for pure fatty acids or mixtures with the highest cis-double bond content. Moreover, the T2 values for each domain exhibited positive linear correlations with fluidity. The TD-NMR T2 and fluidity measurements appear to be monitoring the same underlying phenomenon: variations in hydrocarbon chain packing. The results from this study validate the use of benchtop TD-NMR T2 as a nanofluidity meter and demonstrate its potential for probing nanofluidity in other systems of biological interest.
potential of membrane cholesterol in non-inflamed primary dermal human fibroblasts is z À2.3 kBT relative to crystalline cholesterol. Treating these cells with tumor necrosis factor (TNF-a) for 72 hr results in an increase of the chemical potential. This increase occurs in a dose-dependent manner: modest for 10 ng/ml TNF-a, about 0.8 kBT greater for 20 ng/ml, and only slightly greater for 40 ng/ml. Simultaneous treatment with TNF-a and 50 nM of the antiinflammatory agent dexamethasone abolishes the increase in the chemical potential of cholesterol caused by TNF-a alone. Using 5 ng/ml of interleukin-1b, instead of TNF-a, as a pro-inflammatory agent also resulted in a rise of chemical potential. But the effect was less than that induced by TNF-a; the increase was z 0.5 kBT. These results indicate a possible causative relation between cell inflammation and the chemical potential of plasma membrane cholesterol. Supported by R01 GM101539.
Current proteomic strategies exploit the measurement of hundreds-to-thousands of potential biomarkers to establish profiles of disease risk. We propose an alternative strategy - inverse proteomics - which utilizes just one marker to monitor the status of many biomolecules all at once. Water is an attractive surveillance system, as it forms hydrogen bonds with virtually every protein, lipoprotein and metabolite in human blood. Here we show that the mobility of water in plasma and serum samples from apparently healthy human subjects correlates with known markers of inflammation, insulin resistance, dyslipidemia and possibly, oxidative stress. Water mobility is assessed in a six-minute experiment that requires no sample manipulations or chemical reactions. Rather, the spin-spin relaxation time constant (T 2 ) is measured non-invasively using benchtop time-domain nuclear magnetic resonance. The current discovery provides a framework for developing a simple blood test that could identify individuals with hidden risk for diabetes, atherosclerosis and Alzheimer’s disease.
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