Angeliki Georgopoulos

Synchronous neural interactions assessed by magnetoencephalography: a functional biomarker for brain disorders

We report on a test to assess the dynamic brain function at high temporal resolution using magnetoencephalography (MEG). The essence of the test is the measurement of the dynamic synchronous neural interactions, an essential aspect of the brain function. MEG signals were recorded from 248 axial gradiometers while 142 human subjects fixated a spot of light for 45-60 s. After fitting an autoregressive integrative moving average (ARIMA) model and taking the stationary residuals, all pairwise, zero-lag, partial cross-correlations (PCC(ij)(0)) and their z-transforms (z(ij)(0)) between i and j sensors were calculated, providing estimates of the strength and sign (positive, negative) of direct synchronous coupling at 1 ms temporal resolution. We found that subsets of z(ij)(0) successfully classified individual subjects to their respective groups (multiple sclerosis, Alzheimers disease, schizophrenia, Sjögrens syndrome, chronic alcoholism, facial pain, healthy controls) and gave excellent external cross-validation results.

Differences in the Metabolism of Postprandial Lipoproteins After a High-Monounsaturated-Fat Versus a High-Carbohydrate Diet in Patients With Type 1 Diabetes Mellitus

There is little information comparing the effects of a high-monounsaturated (Mono)-fat versus a high-carbohydrate (CHO) diet in patients with type 1 diabetes mellitus. In the present study, the effects of these diets on a number of metabolic parameters were compared. Seventeen normolipidemic, nonobese patients with type 1 diabetes were provided with the diets for 4 weeks each in a randomized, crossover design. The percentages of Mono fat of the two diets were 25 Mono versus 9 CHO, with a corresponding total fat content of 40% versus 24% and a total CHO content of 45% versus 61%. At the end of each dietary period, parameters of glycemic control, coagulation factors, and fasting and postprandial lipoproteins were assessed. There were no differences in weight, glycemia, insulin dose, fasting lipid profile, or coagulation factors between the two diets. However, the metabolism of postprandial lipoproteins after a fat load differed; viz, after the Mono diet compared with the CHO diet, mean plasma triglyceride levels over 10 hours were higher (P=.0025, by repeated-measures ANOVA). The levels of triglyceride (P=.0045) and retinyl esters (P=.0046) in chylomicrons (Sf>400) and chylomicron remnants (Sf 100 to 400) (P=.0047 and P=.043, respectively), and the total particle number (apolipoprotein B levels) in chylomicron remnants (P=.001) and small, very low density lipoprotein (Sf 20 to 100, P=.016) were also higher. Our data suggest that in patients with type 1 diabetes, a CHO diet might be preferable to a Mono diet, since adherence to the former results in a lower number of circulating postprandial lipoprotein particles that are potentially atherogenic.

Diabetic postprandial triglyceride-rich lipoproteins increase esterified cholesterol accumulation in THP-1 macrophages.

The risk of cardiovascular disease is increased in subjects with insulin-dependent diabetes mellitus (IDDM), although the mechanism remains unclear. To assess whether diabetic postprandial triglyceride (TG)-rich lipoprotein (TGRLP) subfractions (Sf > 400, 100-400, and 20-100) isolated from non-obese, normolipidemic IDDM subjects (n = 14) are potentially more atherogenic than lipoproteins from normal controls (n = 13), we measured cholesteryl ester (CE) synthesis and esterified cholesterol (EC) mass accumulation in THP-1 macrophages incubated with postprandial TGRLP. Diabetic Sf > 400 and Sf 100-400 but not Sf 20-100 significantly increased the mean (+/- SE) rate (pmol/mg cell protein/24 h) of CE synthesis in THP-1 macrophages compared with normal controls (Sf > 400, 673 +/- 26 v 301 +/- 64, P < .025; Sf 100-400, 560 +/- 27 v 298 +/- 39, P < .0005; Sf 20-100, 743 +/- 51 v 831 +/- 45). As well, all three diabetic TGRLP increased the mass of EC (microgram EC/mg cell protein/48 h) as compared with normal controls (Sf > 400, 4.9 +/- 0.61 v 2.9 +/- 0.50, P < .025; Sf 100-400, 5.7 +/- 0.91 v 3.4 +/- 0.34, P < .05; Sf 20-100, 5.4 +/- 0.7 v 3.2 +/- 0.52, P < .05). This effect is sustained for at least 7 hours postprandially and is greater than that of fasting Sf 100-400 (P < .03) and Sf 20-100 (P < .05) and similar to malondealdehyde low-density lipoprotein (MDA-LDL). To assess the mechanisms involved, the chemical composition and cellular degradation of diabetic and control lipoproteins were compared. Postprandial diabetic Sf 100-400 had abnormal composition (phospholipid to protein ratio, 1.86 +/- 0.14 v 1.5 +/- 0.13, P < .05) and in preliminary experiments demonstrated increased cell association (mean +/- SD at 6 hours, 126 +/- 34.3 v 57 +/- 4.2) and degradation (584 +/- 141 v 254 +/- 13) compared with that of normal controls, and may account for the observed increase in EC accumulation. In summary, postprandial diabetic Sf > 400 and Sf 100-400 TGRLP increase CE synthesis and Sf > 400, Sf 100-400, and Sf 20-100 lipoproteins increase EC accumulation in human macrophages compared with normal control lipoproteins. Diabetic Sf 100-400 lipoproteins have abnormal composition and seem to have increased cellular association and degradation compared with normal lipoproteins. Our findings suggest a role for postprandial TGRLP in the increased risk of cardiovascular disease among subjects with IDDM.

Decreased postprandial response to a fat meal in normotriglyceridemic men with hypoalphalipoproteinemia.

The plasma level of high density lipoprotein cholesterol (HDL-C) has been reported to be inversely correlated with the level of triglycerides (TGs) and the magnitude of postprandial lipemia because subjects with low HDL-C accompanying high TG levels often have an increased postprandial response to a fat load. However, information is limited regarding the postprandial response to a fat load in subjects with low HDL-C and normal fasting TG values (hypoalphalipoproteinemia [hypoalpha]). We administered an oral fat load (70 g/m2 of body surface area) to six subjects with hypoalpha and six aged-matched control subjects. Plasma levels of lipids and lipoproteins and the mass of triglyceride-rich lipoproteins (TRLs: Sf > 100 and Sf 20-100) were measured every 2 hours for 8 hours. The mass and chemical composition of Sf > 100 or Sf 20-100 TRLs were not different between the fasting groups; postprandial Sf > 100 but not Sf 20-100 TRLs (mean +/- SD) was significantly lower in subjects with hypoalpha (200.4 +/- 64.8 mg/dL versus 110.6 +/- 50.9 mg/dL; analysis of variance, F test, p = 0.04). In the hypoalpha subjects, the compositions of postprandial Sf > 100 TRLs were TG poor and cholesterol and phospholipid enriched (p < 0.001) while the Sf 20-100 TRLs were enriched in cholesterol and phospholipid but relatively protein depleted (p = 0.002).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of Desirable Fasting Triglycerides on the Postprandial Response to Dietary Fat

Background The National Cholesterol Education Program (NCEP) recently revised the “desirable” fasting triglyceride (TG) to < 150 mg/dL, and levels exceeding 200 mg/dL are defined as “high.” Methods To evaluate the postprandial response to dietary fat, 50 studies were conducted in nonobese, normocholesterolemic subjects. Following an overnight fast, subjects consumed an oral fat load (70 g/m2), and postprandial triglyceride (ppTG) measurements were assessed at 2, 4, 6, and 8 hours. Subjects were divided by fasting TG cutpoints of 100 and 150 mg/dL. Results The prevalence of ppTG samples exceeding 200 mg/dL was significantly lower with fasting TG < 100 mg/dL (n = 116) compared with TG 100 to 150 mg/dL (n = 56) (8% versus 25%; p = .004, chi-square analysis). In addition, fasting TG < 100 mg/dL (n = 29) was associated with a reduced mean 4-hour peak ppTG level compared with fasting TG > 100 mg/dL (n = 21) (125 mg/dL versus 249.8 mg/dL; p < .0001). Multiple linear regression analysis identified fasting TG as the most important determinant of the postprandial response after adjustment for other covariates (p = .0005). Conclusions Because ppTG-rich lipoproteins contribute to coronary heart disease risk, fasting TG < 100 mg/dL may be a more desirable cutpoint than fasting TG < 150 mg/dL in coronary heart disease risk factor assessment.

The number of cysteine residues per mole in apolipoprotein E affects systematically synchronous neural interactions in women’s healthy brains

Apolipoprotein E (apoE) is involved in lipid metabolism in the brain, but its effects on brain function are not understood. Three apoE isoforms (E4, E3, and E2) are the result of cysteine–arginine interchanges at two sites: there are zero interchanges in E4, one interchange in E3, and two interchanges in E2. The resulting six apoE genotypes (E4/4, E4/3, E4/2, E3/3, E3/2, E2/2) yield five groups with respect to the number of cysteine residues per mole (CysR/mole), as follows. ApoE4/4 has zero cysteine residues per mole (0-CysR/mole), E4/3 has one (1-CysR/mole), E4/2 and E3/3 each has two (2-CysR/mole), E3/2 has three (3-CysR/mole), and E2/2 has four (4-CysR/mole). The use of the number of CysR/mole to characterize the apoE molecule converts the categorical apoE genotype scale, consisting of 6 distinct genotypes above, to a 5-point continuous scale (0–4 CysR/mole). This allows the use of statistical analyses suitable for continuous variables (e.g. regression) to quantify the relations between various variables and apoE. Using such analyses, here, we show for the first time that apoE affects in a graded and orderly manner neural communication, as assessed by analyzing the relation between the number of CysR/mole and synchronous neural interactions (SNI) measured by magnetoencephalography (MEG) in 130 cognitively healthy women. At the one end of the CysR/mole range, the 4-CysR/mole (E2/2) SNI distribution had the highest mean, lowest variance, lowest range, and lowest coefficient of variation, whereas at the other end, 0-CysR/mole (E4/4) SNI distribution had the lowest mean, highest variance, highest range, and highest coefficient of variation. The special status of the 4-CysR/mole distribution was reinforced by the results of a hierarchical tree analysis where the 4-CysR/mole (E2/2) SNI distribution occupied a separate branch by itself and the remaining CysR/mole SNI distributions were placed at increasing distances from the 4-CysR/mole distribution, according to their number of CysR/mole, with the 0-CysR/mole (E4/4) being farthest away. These findings suggest that the 4-CysR/mole (E2/2) SNI distribution could serve as a reference distribution. When the SNI distributions of individual women were expressed as distances from this reference distribution, there was a substantial overlap among women of various CysR/mole. This refocuses the placement of individual brains along a continuous distance from the 4-CysR/mole SNI distribution, in contrast to the common categorical assignment to a specific apoE genotype. Finally, the orderly variation of SNI with the number of CysR/mole found here is in keeping with recent advances and ideas regarding the molecular mechanisms underlying the differential effects of apoE in the brain which emphasize the healthier stability conferred on the apoE molecule by the increasing number of cysteine–arginine interchanges, with 4-CysR/mole (E2/2) being the best case, as opposed to the instability and increased chance of toxic fragmentation of the apoE molecule with lower number of CysR/mole, with 0-CysR/mole (E4/4) as the worst case (Mahley and Huang in Neuron 76:871–885, 2012a). However, our results also document the appreciable variation of SNI properties within the various CysR/mole groups and individuals which points to the existence and important role of other factors involved in shaping brain function at the network level.

Reduced Human Leukocyte Antigen (HLA) Protection in Gulf War Illness (GWI).

Background Gulf War Illness (GWI) is a disease of unknown etiology with symptoms suggesting the involvement of an immune process. Here we tested the hypothesis that Human Leukocyte Antigen (HLA) composition might differ between veterans with and without GWI. Methods We identified 144 unique alleles of Class I and II HLA genes in 82 veterans (66 with and 16 without GWI). We tested the hypothesis that a subset of HLA alleles may classify veterans in their respective group using a stepwise linear discriminant analysis. In addition, each participant rated symptom severity in 6 domains according to established GWI criteria, and an overall symptom severity was calculated. Findings We found 6 Class II alleles that classified participants 84.1% correctly (13/16 control and 56/66 GWI). The number of copies of the 6 alleles was significantly higher in the control group, suggesting a protective role. This was supported by a significant negative dependence of overall symptom severity on the number of allele copies, such that symptom severity was lower in participants with larger numbers of allele copies. Interpretation These results indicate a reduced HLA protection (i.e. genetic susceptibility) in veterans with GWI. Funding University of Minnesota and U.S. Department of Veterans Affairs.

A high-fat diet and the threonine-encoding allele (Thr54) polymorphism of fatty acid-binding protein 2 reduce plasma triglyceride-rich lipoproteins

The threonine-encoding allele (Thr54) of the fatty acid-binding protein 2 (FABP2) DNA polymorphism is associated with increased triglyceride (TG)-rich lipoproteins (TRL). We hypothesized that the TRL response to diets of varied fat content is affected by the FABP2 A54T polymorphism, specifically that a high-fat diet would reduce TRL and that the Thr54 allele would have an enhanced response. Sixteen healthy, postmenopausal women completed a crossover dietary intervention that included three 8-week, isoenergetic diet treatments. The treatments consisted of high fat (40% of energy as fat), low fat (20% of energy), and low fat + n-3 fatty acids (20% of energy plus 3% as n-3 fatty acids). Eight subjects were homozygous for the wild type (Ala54/Ala54) of the FABP2 polymorphism, whereas 8 subjects had at least 1 Thr54 allele (7, Ala54/Thr54; 1, Thr54/Thr54). High-fat diet showed significantly reduced plasma TGs, chylomicron TG, and very low-density lipoprotein TG from baseline in all participants. Although carriers of the Thr54 allele of the FABP2 polymorphism had significantly reduced TRL, there is no evidence of an interaction, which does not support our hypothesis. The alanine-encoding allele did not influence the dietary effects on the plasma lipids.

A network analysis of developing brain cultures

We recorded electrical activity from four developing embryonic brain cultures (4-40 days in vitro) using multielectrode arrays (MEAs) with 60 embedded electrodes. Data were filtered for local field potentials (LFPs) and downsampled to 1 ms to yield a matrix of time series consisting of 60 electrode × 60 000 time samples per electrode per day per MEA. Each electrode time series was rendered stationary and nonautocorrelated by applying an ARIMA (25, 1, 1) model and taking the residuals (i.e. innovations). Two kinds of analyses were then performed. First, a pairwise crosscorrelation (CC) analysis (±25 1 ms lags) revealed systematic changes in CC with lag, day in vitro (DIV), and inter-electrode distance. Specifically, (i) positive CCs were 1.76× more prevalent and 1.44× stronger (absolute value) than negative ones, and (ii) the strength of CC increased with DIV and decreased with lag and inter-electrode distance. Second, a network equilibrium analysis was based on the instantaneous (1 ms resolution) logratio of the number of electrodes that were above or below their mean, called simultaneous departure from equilibrium, SDE. This measure possesses a major computational advantage over the pairwise crosscorrelation approach because it is very simple and fast to calculate, an important factor for the analysis of large networks. The results obtained with SDE covaried highly with CC over DIV, which further validates the usefulness of this measure as a computationally effective tool for large scale network analysis.

Effects of Simvastatin on Fasting and Postprandial Triglyceride-Rich Lipoproteins in Patients with Type I Diabetes Mellitus

To assess the effect of simvastatin on fasting and postprandial triglyceride (TG)-rich lipoproteins in subjects with type 1 diabetes and elevated LDL cholesterol levels, eight patients participated in a simvastatin versus placebo, randomized, crossover study. At the end of each drug period fasting and postprandial lipoprotein studies were undertaken. Fasting plasma total and LDL cholesterol and apolipoprotein B (apo B) were significantly lower on simvastatin compared to placebo. Postprandial studies: simvastatin versus placebo consistently decreased the area under the curve (AUC, mean+/-SEM) of TG in plasma (12.52+/-9.07 versus 18.70+/-10.48 mmol x h/L, p = 0.02). Similarly, TG AUC was lower: in the chylomicron subfraction (Sf > 400) 3.24+/-2.71 versus 5.27+/-4.61 mmol x h/L p = 0.03; and in the [chylomicron remnant + VLDL] subfraction (Sf 20-400) 3.98+/-2.51 versus 7.04+/-3.88 mmol x h/L, p = 0.01. This was due to decreased particle n umber rather than size, as shown by a decrease in the AUC of apo B in Sf 20-400 (600+/-360 versus 980+/-600 mg x h/L, p = 0.02) and the lack of change in the ratio of TG/apo B. Intestinal lipoproteins contributed to the simvastatin effect, as shown by the lower AUC of retinyl esters in both subfractions. Chylomicrons: 627.61+/-363.43 versus 948.19+/-568.34 nmol x h/L, p = 0.02 and remnants: 129.23+/-67.12 versus 208.49+/-92.11 nmol x h/L, p = 0.04. Our data suggest an additional mechanism by which simvastatin can decrease the risk of atherosclerosis in patients with type I diabetes: a decrease of the number of circulating intestinal and hepatic postprandial TG-rich lipoprotein particles.