Relative Metabolite Concentrations Research Articles

Noise-reduction techniques for 1H-FID-MRSI at 14.1 T: Monte Carlo validation and in vivo application.

Proton magnetic resonance spectroscopic imaging (1H-MRSI) is a powerful tool that enables the multidimensional non-invasive mapping of the neurochemical profile at high resolution over the entire brain. The constant demand for higher spatial resolution in 1H-MRSI has led to increased interest in post-processing-based denoising methods aimed at reducing noise variance. The aim of the present study was to implement two noise-reduction techniques, Marchenko-Pastur principal component analysis (MP-PCA) based denoising and low-rank total generalized variation (LR-TGV) reconstruction, and to test their potential with and impact on preclinical 14.1 T fast in vivo 1H-FID-MRSI datasets. Since there is no known ground truth for in vivo metabolite maps, additional evaluations of the performance of both noise-reduction strategies were conducted using Monte Carlo simulations. Results showed that both denoising techniques increased the apparent signal-to-noise ratio (SNR) while preserving noise properties in each spectrum for both in vivo and Monte Carlo datasets. Relative metabolite concentrations were not significantly altered by either method and brain regional differences were preserved in both synthetic and in vivo datasets. Increased precision of metabolite estimates was observed for the two methods, with inconsistencies noted for lower-concentration metabolites. Our study provided a framework for how to evaluate the performance of MP-PCA and LR-TGV methods for preclinical 1H-FID MRSI data at 14.1 T. While gains in apparent SNR and precision were observed, concentration estimations ought to be treated with care, especially for low-concentration metabolites.

Increased α-ketoglutarate links the C3-C4 intermediate state to C4 photosynthesis in the genus Flaveria.

As a complex trait, C4 photosynthesis has multiple independent origins in evolution. Phylogenetic evidence and theoretical analysis suggest that C2 photosynthesis, which is driven by glycine decarboxylation in the bundle sheath cell, may function as a bridge from C3 to C4 photosynthesis. However, the exact molecular mechanism underlying the transition between C2 photosynthesis to C4 photosynthesis remains elusive. Here, we provide evidence suggesting a role of higher α-ketoglutarate (AKG) concentration during this transition. Metabolomic data of 12 Flaveria species, including multiple photosynthetic types, show that AKG concentration initially increased in the C3-C4 intermediate with a further increase in C4 species. Petiole feeding of AKG increases the concentrations of C4-related metabolites in C3-C4 and C4 species but not the activity of C4-related enzymes. Sequence analysis shows that glutamate synthase (Fd-GOGAT), which catalyzes the generation of glutamate using AKG, was under strong positive selection during the evolution of C4 photosynthesis. Simulations with a constraint-based model for C3-C4 intermediate further show that decreasing the activity of Fd-GOGAT facilitated the transition from a C2-dominant to a C4-dominant CO2 concentrating mechanism. All these results provide insight into the mechanistic switch from C3-C4 intermediate to C4 photosynthesis.

Preliminary study on early diagnosis of Alzheimer's disease in APP/PS1 transgenic mice using multimodal magnetic resonance imaging.

Alzheimer's disease (AD) has an insidious onset and lacks clear early diagnostic markers, and by the time overt dementia symptoms appear, the disease is already in the mid-to-late stages. The search for early diagnostic markers of AD may open a critical window for Alzheimer's treatment and facilitate early intervention to slow the progression of AD. In this study, we aimed to explore the imaging markers for early diagnosis of AD through the combined application of structural magnetic resonance imaging (sMRI), resting-state functional magnetic resonance imaging (rs-fMRI), and 1H-magnetic resonance spectroscopy (1H-MRS) multimodal magnetic resonance imaging (MRI) techniques at the animal experimental level, with the aim to provide a certain reference for early clinical diagnosis of AD. First, sMRI scans were performed on 4-month-old amyloid beta precursor protein/presenilin 1 (APP/PS1) transgenic AD model mice and wild type mice of the same litter using a 7.0 T animal MRI scanner to analyze the differential brain regions with structural changes in the gray matter of the brain by voxel-based morphometry (VBM). Next, rs-fMRI scans were performed to analyze the differential brain regions between groups for local spontaneous brain activity and functional connectivity (FC) between brain regions. Finally, 1H-MRS scans were performed to quantify and analyze intergroup differences in the relative concentrations of different metabolites within regions of interest (cortex and hippocampus). Compared with wild type mice, the volume of the left hippocampus, and right olfactory bulb of APP/PS1 transgenic AD model mice were reduced, the functional activity of the bilateral hippocampus, right piriform cortex and right caudate putamen was reduced, the functional network connectivity of the hippocampus was impaired, and the relative content of N-acetylaspartate (NAA)in the hippocampus was decreased. In addition, this study found that imaging changes in olfactory-related brain regions were closely associated with AD diagnosis, and these findings may provide some reference for the early diagnosis of AD.

Previous infestation by conspecifics leads to a transient increase of the performance of Sitobion avenae aphids on wheat leaves

Abstract The ecological niche of aphids is largely defined by the phloem sap of plants, which they consume. Previous studies revealed that aphids may change the phloem sap metabolome and that a previous aphid infestation may benefit them. As aphids reproduce parthenogenetically, the performance and preference of aphids of the same monoclonal aphid lineage can be compared between previously uninfested and previously aphid‐infested plants. Wheat (Triticum aestivum) leaves were infested by clonal lineages of Sitobion avenae aphids for 9–10 days. Leaf phloem exudates were analysed using amino acid profiling and metabolic fingerprinting, capturing mainly specialised metabolites. It was investigated whether aphid colony sizes differ between leaves that were previously uninfested or infested by aphids of a different clonal lineage or by aphids of the same clonal lineage and whether aphids show a preference for any of these leaves. The relative concentrations of metabolites in the phloem exudates were not affected by aphid infestation. Aphid colonies were partly larger on previously aphid‐infested leaves than on control leaves. However, this effect was transient and finally colonies had similar sizes. Given a choice between previously aphid‐infested and uninfested leaves, S. avenae nymphs showed no preferences. The findings that positive effects of previous aphid infestation on aphid performance are transient and that the performance but not the preference of the aphids was affected by previous aphid infestation highlight the temporal dynamics and complexity of aphid–plant interactions. Niche alteration processes may be partly involved in these interactions.

UHPLC-Q-Orbitrap-HRMS-based untargeted metabolomics reveal metabolites change in Justicia gendarussa and its antioxidant capacity at different doses of nitrogen fertilizer.

This study delves into the antioxidant potential of Justicia gendarussa, commonly known as gendarussa, and its response to varying doses of nitrogen fertilizer. Gendarussa exhibits the potential for antioxidant activity. The diverse ecological conditions in which it thrives may influence its biological activity and lead to inconsistent production of secondary metabolites. Nitrogen, a pivotal factor in secondary metabolite production in plants, has become a focal point of this research. This research aims to determine the optimal nitrogen fertilizer dose on gendarussa antioxidant capacity and metabolites using a metabolomics approach. Employing a randomized block design for cultivation, the investigation revealed that a maximum harvest weight of 10.9 g/aerial parts of the plant was achieved with 270 kg/ha of nitrogen fertilizer. This study explored the DPPH, ABTS, FRAP, and CUPRAC assays of antioxidant effect, and found insignificant differences between the various nitrogen treatments. UHPLCQ-Orbitrap HRMS was employed to identify 30 metabolites in positive and 18 in negative ionization modes. Gendarusin A, a major metabolite in gendarussa, is identified in both positive and negative ionization. PCA and heatmap analysis successfully categorized these metabolites in the aerial parts of gendarussa at different nitrogen fertilizer dosages. Based on the metabolomics approach, variations in nitrogen fertilizer made metabolites at doses of 90 kg/ha had higher relative concentrations of metabolites compared to doses of 180 kg/ha and 270 kg/ha. So, 90 kg/ha are the optimal nitrogen fertilizer dose for cultivation and utilization strategies.

Misalignment in circadian‐regulated glymphatic clearance as a driver of neurodegeneration

AbstractBackgroundGlymphatic system (GS) is a glial‐dependent perivascular network that under circadian regulation (Hablitz et al, 2020) controls the clearance of waste products in the central nervous system during the sleep (Xie et al, 2013) and its function is suppressed in several neurodegenerative diseases. Our aim is to investigate whether alteration in the circadian‐controlled dynamics of the GS may be the linker between the periphery and the brain. Our hypothesis is that the disruption of the gut‐brain dialogue, due to peripheral colonic inflammation, alters the circadian clockwork both in periphery and CNS, thereby impacting on the circadian‐regulated GS flux in the brain.MethodThe peripheral inflammation was obtained using an acute dextran sulfate sodium (DSS) mouse model of colitis. Alterations in GS dynamics and in the relative concentrations of selected metabolites in the brain have been evaluated by MRI and MRS, respectively. Aquaporin‐4, α‐syntropin, Connexin‐43 as well as clock genes expression have been assessed in colon, and in different brain areas, by real‐time PCR. AQP4 mis‐location has been evaluated by transmission electron microscopy.ResultOur data demonstrate that, in DSS‐driven acute colitis model, the inflammatory hit strongly impacts on the circadian clockwork both at peripheric and central level, by altering the expression of the core clock components. Such alteration in the clock components expression pattern correlates with changes in GS dynamics in the brain. In particular, colonic inflammation impacts on the expression of astrocyte aquaporin‐4, as well as of α‐syntropin and Connexin‐43, in both cerebellum and cortex, thus suggesting a potential molecular derangement in the regulation of glymphatic influx. Alterations in GS dynamics have also been detected in the relative concentrations of specific metabolites in selective brain areas by MRS. As a consequence of brain changes in GS dynamics, we observed an increased phospho‐tau deposition in the hippocampus of DSS mice.ConclusionThe characterization of the cascade of events and the relationship among gut inflammation, glymphatic influx alteration and brain waste product deposition has a novel significance since it will allow understanding how a persistent peripheral enteric hit may disorganize a central hierarchy thus triggering a self‐sustaining process prodromal of neurodegeneration.

Increasing coverage of the urinary polar metabolome using ultra high-performance hydrophobic interaction liquid chromatography combined with linear and cyclic travelling wave ion mobility and mass spectrometry

The use of HILIC-based separations for the analysis of polar metabolites in metabolic phenotyping studies is well established. Here, we demonstrate the increased coverage of the polar metabolome obtained by travelling wave (TW) ion mobility (IM) instruments combined with HILIC and mass spectrometry (MS) for metabotyping rat and mouse urine samples. Profiling was performed using either a linear TW IM-MS based instrument with a path length of 40 cm or an instrument with a cyclic travelling wave analyser (cIM) with a path length of 95 cm. Due to the added resolution afforded by using both the linear and cyclic IM geometries with MS detection (IM-MS) significant increases in feature count (m/z-tR pairs) were generally obtained compared to HILIC-MS alone. In addition, the use of both linear and cyclic IM-MS improved the quality of the mass spectra obtained as a result of the separation of co-eluting analytes. As would be expected from the increased path length of the cyclic IM-MS instrument compared to the linear device, the largest gains in feature detection were obtained for the HILIC-cIM-MS combination. By increasing the resolution of coeluting components, the cyclic IM-MS instrumentation also provided the largest improvement in the quality of the mass spectral data obtained. When applied to mouse urines obtained from both control and gefitinib-dosed mice, time-related changes were detected in those obtained from the treated animals that were not seen in the controls. Polar metabolites affected by drug administration included, but were not limited to, hypoxanthine, 1,3-dimethyluracil and acetylcarnitine. The changes seen in the relative concentrations of these endogenous metabolites appeared to be related to drug concentrations in the plasma and urine suggesting a pharmacometabodynamic link.

Evaluation of the diagnostic utility on 1.5T and 3.0T 1H magnetic resonance spectroscopy for temporal lobe epilepsy

Background1H magnetic resonance spectroscopy (1H-MRS) can be used to study neurological disorders because it can be utilized to examine the concentrations of related metabolites. However, the diagnostic utility of different field strengths for temporal lobe epilepsy (TLE) remains unclear. The purpose of this study is to make quantitative comparisons of metabolites of TLE at 1.5T and 3.0T and evaluate their efficacy.MethodsOur retrospective collections included the single-voxel 1H-MRS of 23 TLE patients and 17 healthy control volunteers (HCs) with a 1.5T scanner, as well as 29 TLE patients and 17 HCs with a 3.0T scanner. Particularly, HCs were involved both the scans with 1.5T and 3.0T scanners, respectively. The metabolites, including the N-acetylaspartate (NAA), creatine (Cr), and choline (Cho), were measured in the left or right temporal pole of brain. To analyze the ratio of brain metabolites, including NAA/Cr, NAA/Cho, NAA/(Cho + Cr) and Cho/Cr, four controlled experiments were designed to evaluate the diagnostic utility of TLE on 1.5T and 3.0T MRS, included: (1) 1.5T TLE group vs. 1.5T HCs by the Mann-Whitney U Test, (2) 3.0T TLE group vs. 3.0T HCs by the Mann-Whitney U Test, (3) the power analysis for the 1.5T and 3.0T scanner, and (4) 3.0T HCs vs. 1.5T HCs by Paired T-Test.ResultsThree metabolite ratios (NAA/Cr, NAA/Cho, and NAA/(Cho + Cr) showed the same statistical difference (p < 0.05) in distinguishing the TLE from HCs in the bilateral temporal poles when using 1.5T or 3.0T scanners. Similarly, the power analysis demonstrated that four metabolite ratios (NAA/Cr, NAA/Cho, NAA/(Cho + Cr), Cho/Cr) had similar distinction abilities between 1.5T and 3.0T scanner, denoting both 1.5T and 3.0T scanners were provided with similar sensitivities and reproducibilities for metabolites detection. Moreover, the metabolite ratios of the same healthy volunteers were not statistically different between 1.5T and 3.0T scanners, except for NAA/Cho (p < 0.05).Conclusions1.5T and 3.0T scanners may have comparable diagnostic potential when 1H-MRS was used to diagnose patients with TLE.

Abstract 393: Distribution and Elimination Kinetics of Midazolam and Metabolites in Patients With Post-Cardiac Arrest Care

Background: Administration of midazolam (MDZ) can make neuroprognostication more complex, especially in determining the safe timing for avoiding inappropriately pessimistic prognostications. This study aims to investigate the distribution and elimination kinetics of MDZ and metabolites in patients with post-resuscitation care. Methods: This was a prospectively observational study between May 2020 and April 2022. Samples for analyzing plasma concentration of MDZ and seven metabolites were obtained immediately, at 4, 8, 12, and 24 h from discontinuation of MDZ infusion. Briefly, absolute and relative concentrations of MDZ and metabolites were determined by LC-MS/MS and LC-QTOF. The area under the plasma concentration-time curve from time 0 to last measurable time point (AUC last ) and estimated half-life ( t 1/2 ) were calculated according to pharmacokinetic rules. Results: Of the 13 enrolled patients, 8 (61.5%) awakened after discontinuation of MDZ administration. MDZ, 1-hydroxylmidazolam (1-OH-MDZ), 1-hydroxylmidazolam-glucuronide (1-OH-MDZ-Glu), and midazolam-glucuronide (MDZ-Glu) were identified as the major compounds, comprising approximately 96% of the total proportion. All compounds had individual mean t 1/2 (MDZ, 1-OH-MDZ, 1-OH-MDZ-Glc, and MDZ-Glc: 6.4, 7.6, 14.3, and 10.5 h, respectively). In the subgroup analysis for the awakened patients, the significant correlation between AUC last and awakening time measured from discontinuation of MDZ infusion was demonstrated in MDZ (r 2 = 0.66) and 1-OH-MDZ (r 2 = 0.55). Conclusions: Even in the normothermia state of the patients, t 1/2 of MDZ and metabolites was prolonged compared with that reported in healthy individuals. Among all compounds, MDZ and 1-OH-MDZ concentrations may be mainly active compounds related to the sedation effect. Hence, to prevent inappropriate WLST for patients with potential for recovery, we recommend clinicians consider the prolonged t 1/2 of the main active compounds.

FRI607 SGLT2 Inhibition Improves Muscle Oxidative Capacity And Its Relationship With Cardiac Performance In Patients With T2D And Heart Failure

Abstract Disclosure: Y. Qin: None. N.D. Sanchez: None. A.J. Moody: None. F.M. Acosta: None. S. Neppala: None. M. Brown: None. H. Honka: None. B. Todd: None. L.A. Cruz Moreno: None. A.R. Stepanenko: None. S.E. Espinoza: None. N. Musi: None. C. Triplitt: None. G. Clarke: None. E. Cersosimo: None. R.A. DeFronzo: None. C. Solis-Herrera: None. Cardioprotective benefits of SGLT2 inhibitors (SGLT2i) have been largely thought to be coupled to a physiologic increase in plasma ketones, with much interest in the role of adaptive changes in cardiac fuel source in subjects with T2D and HF. Given the changes in the global dynamics of bioenergetics with SGLT2i, and the proven pleiotropic effects of ketone bodies, suggest that, in addition to their cardioprotective function, SGLT2i may influence other organ systems. In particular, how skeletal muscle (SkM), or cardiopulmonary function, respond to these global bioenergetics changes remains largely unknown. A pilot randomized-controlled clinical study was designed to examine the effects of SGLT2i on SkM bioenergetics (31P MRS), &amp; cardiopulmonary function (CPET), and its association with left ventricular cardiac function (MRI). Six subjects (Age=59±2.6, BMI=33.3±1.1, A1c=7.1±0.3) with T2D and HF (&amp;lt;50%) were randomized empagliflozin 25mg/day (SGLT2i) vs. placebo (control) in a 2:1 fashion for 12 weeks. Imaging and clinical evaluations were performed pre- and post-intervention. The SGLT2i group improved EF (28.7 vs. 38.8, p=0.1). SkM 31P MRS at rest, measuring the relative intracellular concentrations of high-energy metabolites of phospholipid breakdown, reduced with SGLT2i, suggesting better energy utilization by the SkM. 31P MRS-after exercise, showed significant improvements in SkM oxidative capacity (KPCR*[PCr], 0.6 to 0.8, p=0.03), with SGLT2i.During CPET testing, the ventilatory anaerobic threshold (VT), with SGLT2i, showed a significant (p=0.05) increase in VT time, suggesting an increase in the time in aerobiosis in these subjects. The minute ventilation-to-carbon dioxide output slope (a strong predictor of cardiopulmonary complications/death) was improved in the SGLT2i group vs. placebo, which could be associated with the CV benefit observed with these agents. Additionally, patient self-reported outcomes (Promis) showed a trend of improvement in the SGLT2i group. In summary, we demonstrate novel and exciting preliminary findings that in patients with T2D &amp; HF, SGLT2i-associated benefits are not isolated to the heart and may also expand to the SkM, including improved oxidative capacity, energy utilization, and SkM recovery post-exercise. With improvements in HF prognostic markers and patient self-reported outcomes. These original findings may represent novel mechanisms contributing to the cardiac benefits of SGLT2i. Presentation: Friday, June 16, 2023

Non-invasive biomarkers for mild cognitive impairment and Alzheimer's disease

Alzheimer's disease is the most common type of dementia in the elderly. It is a progressive degenerative disorder that may begin to develop up to 15 years before clinical symptoms appear. The identification of early biomarkers is crucial to enable a prompt diagnosis and to start effective interventions. In this work, we conducted a metabolomic study using proton Nuclear Magnetic Resonance (1H NMR) spectroscopy in serum samples from patients with neuropathologically confirmed Alzheimer's disease (AD, n = 51), mild cognitive impairment (MCI, n = 27), and cognitively healthy controls (HC, n = 50) to search for metabolites that could be used as biomarkers. Patients and controls underwent yearly clinical follow-ups for up to six years. MCI group included samples from three subgroups of subjects with different disease progression rates. The first subgroup included subjects that remained clinically stable at the MCI stage during the period of study (stable MCI, S-MCI, n = 9). The second subgroup accounted for subjects which were diagnosed with MCI at the moment of blood extraction, but progressed to clinical dementia in subsequent years (MCI-to-dementia, MCI-D, n = 14). The last subgroup was composed of subjects that had been diagnosed as dementia for the first time at the moment of sample collection (incipient dementia, Incp-D, n = 4). Partial Least Square Discriminant Analysis (PLS-DA) models were developed. Three models were obtained, one to discriminate between AD and HC samples with high sensitivity (93.75%) and specificity (94.75%), another model to discriminate between AD and MCI samples (100% sensitivity and 82.35% specificity), and a last model to discriminate HC and MCI with lower sensitivity and specificity (67% and 50%). Differences within the MCI group were further studied in an attempt to determine those MCI subjects that could develop AD-type dementia in the future. The relative concentration of metabolites, and metabolic pathways were studied. Alterations in the pathways of alanine, aspartate and glutamate metabolism, pantothenate and CoA biosynthesis, and beta-alanine metabolism, were found when HC and MCI- D patients were compared. In contrast, no pathway was found disturbed in the comparison of S-MCI with HC groups. These results highlight the potential of 1H NMR metabolomics to support the diagnosis of dementia in a less invasive way, and set a starting point for the study of potential biomarkers to identify MCI or HC subjects at risk of developing AD in the future.

CSF dopamine is elevated in first-episode psychosis and associates to symptom severity and cognitive performance.

The hypothesis of dopamine dysfunction in psychosis has evolved since the mid-twentieth century. However, clinical support from biochemical analysis of the transmitter in patients is still missing. The present study assessed dopamine and related metabolites in the cerebrospinal fluid (CSF) of first-episode psychosis (FEP) subjects. Forty first-episode psychosis subjects and twenty healthy age-matched volunteers were recruited via the Karolinska Schizophrenia Project, a multidisciplinary research consortium that investigates the pathophysiology of schizophrenia. Psychopathology, disease severity, and cognitive performance were rated as well as cerebrospinal fluid concentrations of dopamine and related metabolites were measured using a sensitive high-pressure liquid chromatography assay. CSF dopamine was reliably detected in 50% of healthy controls and in 65% of first-episode psychosis subjects and significantly higher in first-episode psychosis subjects compared to age-matched healthy controls. No difference in CSF dopamine levels was observed between drug-naive subjects and subjects with short exposure to antipsychotics. The dopamine concentrations were positively associated with illness severity and deficits in executive functioning. Dopamine dysfunction has long been considered a cornerstone of the pathophysiology of schizophrenia, although biochemical support for elevated brain dopamine levels has been lacking. The results of the present study, showing that FEP subjects have increased CSF dopamine levels that correlate to disease symptoms, should fill the knowledge gap in this regard.

Machine Learning-Assisted High-Throughput SERS Classification of Cell Secretomes.

During the response to different stress conditions, damaged cells react in multiple ways, including the release of a diverse cocktail of metabolites. Moreover, secretomes from dying cells can contribute to the effectiveness of anticancer therapies and can be exploited as predictive biomarkers. The nature of the stress and the resulting intracellular responses are key determinants of the secretome composition, but monitoring such processes remains technically arduous. Hence, there is growing interest in developing tools for noninvasive secretome screening. In this regard, it has been previously shown that the relative concentrations of relevant metabolites can be traced by surface-enhanced Raman scattering (SERS), thereby allowing label-free biofluid interrogation. However, conventional SERS approaches are insufficient to tackle the requirements imposed by high-throughput modalities, namely fast data acquisition and automatized analysis. Therefore, machine learning methodswereimplemented to identify cell secretome variations while extracting standard features for cell death classification. To this end, ad hoc microfluidic chipsweredevised, to readily conduct SERS measurements through a prototype relying on capillary pumps made of filter paper, which eventually would function as the SERS substrates. The developed strategy may pave the way toward a faster implementation of SERS into cell secretome classification, which can be extended even to laboratories lacking highly specialized facilities.

Physics-informed deep learning approach to quantification of human brain metabolites from magnetic resonance spectroscopy data

PurposeWhile the recommended analysis method for magnetic resonance spectroscopy data is linear combination model (LCM) fitting, the supervised deep learning (DL) approach for quantification of MR spectroscopy (MRS) and MR spectroscopic imaging (MRSI) data recently showed encouraging results; however, supervised learning requires ground truth fitted spectra, which is not practical. Moreover, this work investigates the feasibility and efficiency of the LCM-based self-supervised DL method for the analysis of MRS data. MethodWe present a novel DL-based method for the quantification of relative metabolite concentrations, using quantum-mechanics simulated metabolite responses and neural networks. We trained, validated, and evaluated the proposed networks with simulated and publicly accessible in-vivo human brain MRS data and compared the performance with traditional methods. A novel adaptive macromolecule fitting algorithm is included. We investigated the performance of the proposed methods in a Monte Carlo (MC) study. ResultThe validation using low-SNR simulated data demonstrated that the proposed methods could perform quantification comparably to other methods. The applicability of the proposed method for the quantification of in-vivo MRS data was demonstrated. Our proposed networks have the potential to reduce computation time significantly. ConclusionThe proposed model-constrained deep neural networks trained in a self-supervised manner can offer fast and efficient quantification of MRS and MRSI data. Our proposed method has the potential to facilitate clinical practice by enabling faster processing of large datasets such as high-resolution MRSI datasets, which may have thousands of spectra.

Functional Magnetic Resonance Spectroscopy of Lactate in Alzheimer Disease: A Comprehensive Review of Alzheimer Disease Pathology and the Role of Lactate.

Functional 1H magnetic resonance spectroscopy (fMRS) is a derivative of dynamic MRS imaging. This modality links physiologic metabolic responses with available activity and measures absolute or relative concentrations of various metabolites. According to clinical evidence, the mitochondrial glycolysis pathway is disrupted in many nervous system disorders, especially Alzheimer disease, resulting in the activation of anaerobic glycolysis and an increased rate of lactate production. Our study evaluates fMRS with J-editing as a cutting-edge technique to detect lactate in Alzheimer disease. In this modality, functional activation is highlighted by signal subtractions of lipids and macromolecules, which yields a much higher signal-to-noise ratio and enables better detection of trace levels of lactate compared with other modalities. However, until now, clinical evidence is not conclusive regarding the widespread use of this diagnostic method. The complex machinery of cellular and noncellular modulators in lactate metabolism has obscured the potential roles fMRS imaging can have in dementia diagnosis. Recent developments in MRI imaging such as the advent of 7 Tesla machines and new image reconstruction methods, coupled with a renewed interest in the molecular and cellular basis of Alzheimer disease, have reinvigorated the drive to establish new clinical options for the early detection of Alzheimer disease. Based on the latter, lactate has the potential to be investigated as a novel diagnostic and prognostic marker for Alzheimer disease.

Dietary supplementation with L-citrulline improves placental angiogenesis and embryonic survival in gilts.

This study was conducted with gilts as an animal model to test the hypothesis that dietary supplementation with L-citrulline (Cit) improves placental angiogenesis and embryonic survival. Between Days 14 and 25 of gestation, each gilt was fed a corn- and soybean-meal-based diet (2 kg/day) supplemented with 0.4% Cit or an isonitrogenous amount of L-alanine (Control). On Day 25 of gestation, gilts were hysterectomized to obtain conceptuses. Amniotic and allantoic fluids and placentae were analyzed for NOx [stable oxidation products of nitric oxide (NO)], polyamines, and amino acids (AAs). Placentae were also analyzed for syntheses of NO and polyamines; concentrations of AAs and related metabolites; and the expression of angiogenic factors and aquaporins (AQPs). Compared to the control group, Cit supplementation increased (P < 0.01) the number of viable fetuses by 2.0 per litter, the number and diameter of placental blood vessels (21% and 24%, respectively), placental weight (15%), and total allantoic and amniotic fluid volumes (20% and 47%, respectively). Cit supplementation also increased (P < 0.01) enzymatic activities of GTP-cyclohydrolase-1 (32%) and ornithine decarboxylase (27%) in placentae; syntheses of NO (29%) and polyamines (26%); concentrations of NOx (19%), tetrahydrobiopterin (28%), polyamines (22%), cAMP (26%), and cGMP (24%) in placentae; total amounts of NOx (22-40%), polyamines (23-40%), AAs (16-255%), glucose (22-44%), and fructose (22-43%) in allantoic and amniotic fluids. Furthermore, Cit supplementation increased (P < 0.05) placental mRNA levels for angiogenic factors (eNOS [84%], GTP-CH1 [55%], PGF [61%], VEGFA120 [26%], and VEGFR2 [137%], as well as AQPs - AQP1 [105%], AQP3 [53%], AQP5 [77%], AQP8 [57%], and AQP9 [31%]). Collectively, dietary Cit supplementation enhanced placental NO and polyamine syntheses as well as angiogenesis to improve conceptus development and survival.

What Changes Occur in the Brain of Veteran? A Magnetic Resonance Imaging and Proton Magnetic Resonance Spectroscopy Study

The aims of this study were to assess the common anomalies in the MRI examinations of the heads of soldiers as well as to compare the relative concentration of magnetic resonance spectroscopy (MRS) metabolites in the brains of soldiers with those of healthy age-matched controls. Overall, 54 professional male soldiers were included in the study group and 46 healthy, age-matched males were in the control group. The relative values of N-acetylaspartate (NAA), choline (Cho), and myoinositol (mI) to creatine (Cr) were assessed. The mean relative concentrations of metabolites were compared between the study and the control group, separately for the frontal and occipital lobes, as well as between the right and left hemispheres within the study group only. The most frequent findings in the head MRI of the soldiers were: asymmetric lateral ventricles and dilated perivascular spaces, enlargement of the subarachnoid spaces, and the presence of cavum septum pellucidum and cavum vergae; the high frequency of sinus disease should also be noted. In the frontal lobes, the mI/Cr ratio was significantly higher (p = 0.005), while the NAA/Cr ratio was lower (p = 0.001), in the group of soldiers (vs. the study group). In the occipital lobes, the NAA/Cr ratio was significantly lower (p = 0.005) in the military personnel and there was a tendency to a higher mI/Cr ratio in the soldiers’ occipital lobes (p = 0.056) (vs. the study group). Comparing the metabolites between the left and right hemispheres in soldiers preferring a right shooting position, a significantly higher mI/Cr (p &lt; 0.001) ratio was observed in the right frontal lobe (vs. the left) and a markedly lower NAA/Cr (p = 0.003) in the right occipital lobe (vs. the left). These changes are associated with astrogliosis and neuronal loss, presumably secondary to repetitive mild traumatic brain injury.

Serum concentrations of amino acids and tryptophan metabolites are affected by consumption of a light breakfast: a clinical intervention study in adults with overweight or obesity

BackgroundEpidemiological studies often investigate amino acids and their metabolites as biomarkers, but do not always consistently use fasting or non-fasting blood samples, or may lack information on the prandial status of the study participants. Since little information is available on the effects of the prandial status on many biomarkers, and since blood is typically sampled early in the day with participants in a fasting state or after having consumed a light meal in many trials, the main purpose of this study was to investigate the short-term effects of a light breakfast on serum concentrations of amino acids and related metabolites.MethodsBlood was collected from sixty-three healthy adults (36 women) in the fasting state and at set times for 120 min after intake of a light breakfast with low protein content (14 g protein, 2218 kJ). Relative changes in serum biomarker concentrations from fasting to postprandial serum concentrations were tested using T test.ResultsThe serum concentrations of 13 of the 20 measured amino acids were significantly changed 60 min following breakfast intake, with the most marked effects seen as increases in alanine (34%) and proline (45%) concentrations. The response did not reflect the amino acid composition of the breakfast. The concentrations of seven kynurenine metabolites were significantly decreased after breakfast.ConclusionConsumption of a light breakfast affected serum concentrations of several amino acids and related metabolites, underlining the importance of having information regarding the participants’ prandial state at the time of blood sampling in studies including these biomarkers.Trial registrationThis trial was registered at clinicaltrials.gov as NCT02350595 (registered January 2015).

Spectroscopic analysis of metabolic profile in patients with relapsed multiple sclerosis

Introduction. Managing patients with relapsing-remitting multiple sclerosis (RMS) remains a pressing issue.&#x0D; Objective. To detect the reversible metabolic changes of the brain matter in patients with clinically exacerbated RMS and to follow them up after intravenous glucocorticoid (IVGC) treatment.&#x0D; Materials and methods. Neurological examination and neuroimaging in the RMS patients included expanded disability status scale (EDSS) scoring, conventional brain magnetic resonance imaging (MRI), and proton nuclear magnetic resonance spectroscopy (1H-NMR spectroscopy) before and after IVGC treatment. Multivoxel 1H-NMR spectroscopy was used to assess metabolism in the centra semiovale and cingulate gyri.&#x0D; Results. Based on the multivoxel 1H-NMR spectroscopy, relative metabolite concentrations in the grey and white matter statistically differed within the study cohort before and after the IVGC treatment. The N-acetylaspartate/choline ratio significantly recovered and the choline/creatine ratio decreased in the anterior cingulate gyri in 27% of patients. The brainstem function score significantly improved in the metabolic response group as compared to the non-metabolic response group.&#x0D; Conclusion. We should study the potential predictors of RMS activity and the IVGC response to select the RMS relapses when pulse-therapy with IVGCs is definitely indicated. Spectroscopy may reveal RMS pathogenesis variability earlier than conventional MRI.

Ethnicity Associated Microbial and Metabonomic Profiling in Newly Diagnosed Ulcerative Colitis.

Ulcerative colitis (UC) differs across geography and ethnic groups. Gut microbial diversity plays a pivotal role in disease pathogenesis and differs across ethnic groups. The functional diversity in microbial-driven metabolites may have a pathophysiologic role and offer new therapeutic avenues. Demographics and clinical data were recorded from newly diagnosed UC patients. Blood, urine and faecal samples were collected at three time points over one year. Bacterial content was analysed by 16S rRNA sequencing. Bile acid profiles and polar molecules in three biofluids were measured using liquid-chromatography mass spectrometry (HILIC) and nuclear magnetic resonance spectroscopy. We studied 42 patients with a new diagnosis of UC (27 South Asians; 15 Caucasians) with 261 biosamples. There were significant differences in relative abundance of bacteria at the phylum, genus and species level. Relative concentrations of urinary metabolites in South Asians were significantly lower for hippurate (positive correlation for Ruminococcus) and 4-cresol sulfate (Clostridia) (p<0.001) with higher concentrations of lactate (negative correlation for Bifidobacteriaceae). Faecal conjugated and primary conjugated bile acids concentrations were significantly higher in South Asians (p=0.02 and p=0.03 respectively). Results were unaffected by diet, phenotype, disease severity and ongoing therapy. Comparison of time points at diagnosis and at 1 year did not reveal changes in microbial and metabolic profile. Ethnic-related microbial metabolite associations were observed in South Asians with UC. This suggests a predisposition to UC may be influenced by environmental factors reflected in a distinct gene-environment interaction. The variations may serve as markers to identify risk factors for UC and modified to enhance therapeutic response.