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Traditionally, clinicians consider lactate as a waste product of anaerobic glycolysis. Interestingly, research has shown that lactate may serve as an alternative fuel for the brain to protect it against harm. The increasing scientific awareness of the potential beneficial side of lactate, however, is entering the clinic rather slowly. Following this, and realizing that the application of potential novel therapeutic strategies in pediatric populations often lags behind the development in adults, this review summarizes the key data on therapeutic use of intravenous infusion of sodium lactate in humans. PubMed and clinicaltrial.gov were searched up until November 2021 focusing on interventional studies in humans. Thirty-four articles were included in this review, with protocols of lactate infusion in adults with diabetes mellitus, traumatic brain injury, Alzheimer's disease, and cardiac disease. One study on lactate infusion in children was also included. Results of our literature search show that sodium lactate can be safely administrated, without major side effects. Additionally, the present literature clearly shows the potential benefits of therapeutic lactate infusion under certain pathological circumstances, including rather common clinical conditions like traumatic brain injury.Conclusion: This review shows that lactate is a save, alternative energy source for the adult brain warranting studies on the potential therapeutic effects of sodium lactate infusion in children.

Traditionally, clinicians consider lactate as a waste product of anaerobic glycolysis. Interestingly, research has shown that lactate may serve as an alternative fuel for the brain to protect it against harm. The increasing scientific awareness of the potential beneficial side of lactate, however, is entering the clinic rather slowly. Following this, and realizing that the application of potential novel therapeutic strategies in pediatric populations often lags behind the development in adults, this review summarizes the key data on therapeutic use of intravenous infusion of sodium lactate in humans. PubMed and clinicaltrial.gov were searched up until November 2021 focusing on interventional studies in humans. Thirty-four articles were included in this review, with protocols of lactate infusion in adults with diabetes mellitus, traumatic brain injury, Alzheimer’s disease, and cardiac disease. One study on lactate infusion in children was also included. Results of our literature search show that sodium lactate can be safely administrated, without major side effects. Additionally, the present literature clearly shows the potential benefits of therapeutic lactate infusion under certain pathological circumstances, including rather common clinical conditions like traumatic brain injury.Conclusion: This review shows that lactate is a save, alternative energy source for the adult brain warranting studies on the potential therapeutic effects of sodium lactate infusion in children. What is Known:• Lactate is generally considered a waste product of anaerobic glycolysis. However, lactate also is an alternative fuel for different organs, including the brain.• Lactate infusion is not incorporated in standard care for any patient population. What is New:• Thirty-four studies investigated the therapeutic use of intravenous sodium lactate in different patient populations, all with different study protocols.• Literature shows that lactate infusion may have beneficial effects in case of hypoglycemia, traumatic brain injury, and cardiac failure without the risk of major side effects.

Physical exercise is considered a potent countermeasure against various age-associated physiological deterioration processes. We therefore assessed the effect of 12 weeks of resistance training on brain metabolism in older adults (age range: 60–80 years). Participants either underwent two times weekly resistance training program which consisted of four lower body exercises performed for 3 sets of 6–10 repetitions at 70–85% of 1 repetition maximum (n = 20) or served as the passive control group (n = 21). The study used proton magnetic resonance spectroscopy to quantify the ratio of total N-acetyl aspartate, total choline, glutamate-glutamine complex, and myo-inositol relative to total creatine (tNAA/tCr, tCho/tCr, Glx/tCr, and mIns/tCr respectively) in the hippocampus (HPC), sensorimotor (SM1), and prefrontal (dlPFC) cortices. The peak torque (PT at 60°/s) of knee extension and flexion was assessed using an isokinetic dynamometer. We used repeated measures time × group ANOVA to assess time and group differences and correlation coefficient analyses to examine the pre-to-post change (∆) associations between PT and neurometabolite variables. The control group showed significant declines in tNAA/tCr and Glx/tCr of SM1, and tNAA/tCr of dlPFC after 12 weeks, which were not seen in the experimental group. A significant positive correlation was found between ∆PT knee extension and ∆SM1 Glx/tCr, ∆dlPFC Glx/tCr and between ∆PT knee flexion and ∆dlPFC mIns/tCr in the experimental group. Overall, findings suggest that resistance training seems to elicit alterations in various neurometabolites that correspond to exercise-induced “preservation” of brain health, while simultaneously having its beneficial effect on augmenting muscle functional characteristics in older adults.

People with HIV now have near-normal life expectancies due to the success of effective combination antiretroviral therapy (cART). Following cART initiation, immune recovery occurs, and opportunistic diseases become rare. Despite this, high rates of non-infectious comorbidities persist in treated people with HIV, hypothesized to be related to persistent immuno-activation. One such comorbidity is cognitive impairment, which may partly be driven by ongoing neuro-inflammation in otherwise effectively treated people with HIV. In order to develop therapeutic interventions to address neuro-inflammation in effectively treated people with HIV, a deeper understanding of the pathogenic mechanisms driving persistent neuro-inflammatory responses and the ability to better characterize and measure neuro-inflammation in the central nervous system is required. This review highlights recent advances in molecular neuroimaging techniques which have the potential to assess neuro-inflammatory responses within the central nervous system in HIV disease. Proton magnetic resonance spectroscopy (1H-MRS) has been utilized to assess neuro-inflammatory responses since early in the HIV pandemic and shows promise in recent studies assessing different antiretroviral regimens. 1H-MRS is widely available in both resource-rich and some resource-constrained settings and is relatively inexpensive. Brain positron emission tomography (PET) imaging using Translocator Protein (TSPO) radioligands is a rapidly evolving field; newer TSPO-radioligands have lower signal-to-noise ratio and have the potential to localize neuro-inflammation within the brain in people with HIV. As HIV therapeutics evolve, people with HIV continue to age and develop age-related comorbidities including cognitive disorders. The use of novel neuroimaging modalities in the field is likely to advance in order to rapidly assess novel therapeutic interventions and may play a role in future clinical assessments.

Boron oxide/hydroxide supported on oxidized activated carbon (B/OAC) was shown to be an inexpensive catalyst for the oxidative dehydrogenation (ODH) of propane that offers activity and selectivity comparable to boron nitride. Here, we obtain an atomistic picture of the boron oxide/hydroxide layer in B/OAC by using 35.2 T 11B and 17O solid-state NMR experiments. NMR spectra measured at 35.2 T resolve the boron and oxygen sites due to narrowing of the central-transition powder patterns. A 35.2 T 2D 11B{17O} dipolar heteronuclear correlation NMR spectrum revealed the structural connectivity between boron and oxygen atoms. The approach outlined here should be generally applicable to determine atomistic structures of heterogeneous catalysts containing quadrupolar nuclei. ispartof: Journal Of The American Chemical Society vol:144 issue:41 pages:18766-18771 ispartof: location:United States status: published

Gain-of-function mutations in isocitrate dehydrogenase (IDH) in human cancers result in the production of d -2-hydroxyglutarate ( d -2HG), an oncometabolite that promotes tumorigenesis through epigenetic alterations. The cancer cell–intrinsic effects of d -2HG are well understood, but its tumor cell–nonautonomous roles remain poorly explored. We compared the oncometabolite d -2HG with its enantiomer, l -2HG, and found that tumor-derived d -2HG was taken up by CD8 + T cells and altered their metabolism and antitumor functions in an acute and reversible fashion. We identified the glycolytic enzyme lactate dehydrogenase (LDH) as a molecular target of d -2HG. d -2HG and inhibition of LDH drive a metabolic program and immune CD8 + T cell signature marked by decreased cytotoxicity and impaired interferon-γ signaling that was recapitulated in clinical samples from human patients with IDH1 mutant gliomas.

N-acetylaspartate (NAA) is the second most abundant metabolite in the human brain; although it is assumed to be a proxy for a neuronal marker, its function is not fully elucidated. NAA is also detectable in plasma, but its relation to cerebral NAA levels, cognitive performance, or features of cerebral disease has not been investigated. To study whether circulating NAA tracks cerebral NAA levels, and whether circulating NAA correlates with cognitive function and features of cerebral small vessel disease (SVD). Two datasets were analyzed. In dataset 1, structural MRI was acquired in 533 subjects to assess four features of cerebral SVD. Cognitive function was evaluated with standardized test scores (N = 824). In dataset 2, brain 1H-MRS from the occipital region was acquired (N = 49). In all subjects, fasting circulating NAA was measured with mass spectrometry. Dataset 1: in univariate and adjusted for confounders models, we found no correlation between circulating NAA and the examined features of cerebral SVD. In univariate analysis, circulating NAA levels were associated inversely with the speed in information processing and the executive function score, however these associations were lost after accounting for confounders. In line with the negative findings of dataset 1, in dataset 2 there was no correlation between circulating and central NAA or total NAA levels. This study indicates that circulating NAA levels do not reflect central (occipital) NAA levels, cognitive function, or cerebral small vessel disease in man.

Background: Radiation-induced brain injury is a common long-term side effect for brain cancer survivors, leading to a reduced quality of life. Although there is growing research pertaining to this topic, the relationship between cognitive and radiologically detected lesions of radiation-induced brain injury in humans remains unclear. Furthermore, clinically translatable similarities between rodent models and human findings are also undefined. The objective of this review is to then identify the current evidence of radiation-induced brain injury in humans and to compare these findings to current rodent models of radiation-induced brain injury. Methods: This review includes an examination of the current literature on cognitive and radiological characteristics of radiation-induced brain injury in humans and rodents. A thorough search was conducted on PubMed, Web of Science, and Scopus to identify studies that performed cognitive assessments and magnetic resonance imaging techniques on either humans or rodents after cranial radiation therapy. A qualitative synthesis of the data is herein reported. Results: A total of 153 studies pertaining to cognitively or radiologically detected radiation injury of the brain are included in this systematic review; 106 studies provided data on humans while 47 studies provided data on rodents. Cognitive deficits in humans manifest across multiple domains after brain irradiation. Radiological evidence in humans highlight various neuroimaging-detectable changes post-irradiation. It is unclear, however, whether these findings reflect ground truth or research interests. Additionally, rodent models do not comprehensively reproduce characteristics of cognitive and radiological injury currently identified in humans. Conclusion: This systematic review demonstrates that associations between and within cognitive and radiological radiation-induced brain injuries often rely on the type of assessment. Well-designed studies that evaluate the spectrum of potential injury are required for a precise understanding of not only the clinical significance of radiation-induced brain injury in humans, but also how to replicate injury development in pre-clinical models. Accepted version

Diagnostics : open access journal 12(5), 1202 (2022). doi:10.3390/diagnostics12051202 special issue: "Special Issue "Brain Tumor Imaging" / Special Issue Editors: Dr. Fulvio Zaccagna, Guest EditorDr. Leonardo Rundo, Guest Editor; Dr. James T. Grist, Guest Editor", Published by MDPI, Basel

Gliomas are the most frequent primary tumors of the brain. They can be divided into grade II-IV astrocytomas and grade II-III oligodendrogliomas, based on their histomolecular profile. The prognosis and treatment is highly dependent on grade and well-identified prognostic and/or predictive molecular markers. Multi-parametric MRI, including diffusion weighted imaging, perfusion, and MR spectroscopy, showed increasing value in the non-invasive characterization of specific molecular subsets of gliomas. Radiolabeled amino-acid analogues, such as 18F-FET, have also been proven valuable in glioma imaging. These tracers not only contribute in the diagnostic process by detecting areas of dedifferentiation in diffuse gliomas, but this technique is also valuable in the follow-up of gliomas, as it can differentiate pseudo-progression from real tumor progression. Since multi-parametric MRI and 18F-FET PET are complementary imaging techniques, there may be a synergistic role for PET-MRI imaging in the neuro-oncological imaging of primary brain tumors. This could be of value for both primary staging, as well as during treatment and follow-up.

Background There is an ongoing debate on whether fructose plays a role in the development of nonalcoholic fatty liver disease. Objectives The aim of this study was to investigate the effects of fructose restriction on intrahepatic lipid (IHL) content in a double-blind randomized controlled trial using an isocaloric comparator. Methods Between March 2017 and October 2019, 44 adult overweight individuals with a fatty liver index ≥ 60 consumed a 6-wk fructose-restricted diet (

Rationale and ObjectivesPro-inflammatory processes have been argued to play a role in conditions associated with cognitive decline and neurodegeneration, like aging and obesity. Only a limited number of studies have tried to measure both peripheral and central biomarkers of inflammation and examined their interrelationship. The primary aim of this study was to examine the hypothesis that chronic peripheral inflammation would be associated with neurometabolic changes that indicate neuroinflammation (the combined elevation of myoinositol and choline), brain gray matter volume decrease, and lower cognitive functioning in older adults.Materials and MethodsSeventy-four older adults underwent bio-impedance body composition analysis, cognitive testing with the Montreal Cognitive Assessment (MoCA), blood serum analysis of inflammatory markers interleukin-6 (IL-6) and kynurenine, magnetic resonance imaging (MRI), and proton magnetic resonance spectroscopy (1H-MRS) of the brain. Neurometabolic findings from both Tarquin and LCModel 1H-MRS post-processing software packages were compared. The regions of interest for MRI and 1H-MRS measurements were dorsal posterior cingulate cortex (DPCC), left hippocampal cortex (HPC), left medial temporal cortex (MTC), left primary sensorimotor cortex (SM1), and right dorsolateral prefrontal cortex (DLPFC).ResultsElevated serum kynurenine levels were associated with signs of neuroinflammation, specifically in the DPCC, left SM1 and right DLPFC, and signs of neurodegeneration, specifically in the left HPC, left MTC and left SM1, after adjusting for age, sex and fat percentage (fat%). Elevated serum IL-6 levels were associated with increased Glx levels in left HPC, left MTC, and right DLPFC, after processing the 1H-MRS data with Tarquin. Overall, the agreement between Tarquin and LCModel results was moderate-to-strong for tNAA, tCho, mIns, and tCr, but weak to very weak for Glx. Peripheral inflammatory markers (IL-6 and kynurenine) were not associated with older age, higher fat%, decreased brain gray matter volume loss or decreased cognitive functioning within a cohort of older adults.ConclusionOur results suggest that serum kynurenine may be used as a peripheral inflammatory marker that is associated with neuroinflammation and neurodegeneration, although not linked to cognition. Future studies should consider longitudinal analysis to assess the causal inferences between chronic peripheral and neuroinflammation, brain structural and neurometabolic changes, and cognitive decline in aging.

Cerebral metabolism is tightly regulated and fundamental for healthy neurological function. There is increasing evidence that alterations in this metabolism may be a precursor and early biomarker of later stage disease processes. Proton magnetic resonance spectroscopy (1H-MRS) is a powerful tool to non-invasively assess tissue metabolites and has many applications for studying the normal and diseased brain. However, the technique has limitations including low spatial and temporal resolution, difficulties in discriminating overlapping peaks, and challenges in assessing metabolic flux rather than steady-state concentrations. Hyperpolarized carbon-13 magnetic resonance imaging is an emerging clinical technique that may overcome some of these spatial and temporal limitations, providing novel insights into neurometabolism in both health and in pathological processes such as glioma, stroke and multiple sclerosis. This review will explore the growing body of pre-clinical data that demonstrates a potential role for the technique in assessing metabolism in the central nervous system. There are now a number of clinical studies being undertaken in this area and this review will present the emerging clinical data as well as the potential future applications of hyperpolarized 13C magnetic resonance imaging in the brain, in both clinical and pre-clinical studies.

Background For the same BMI, South Asians have a higher body fat percentage, a higher liver fat content and a more adverse metabolic profile than whites. South Asians may have a lower fat oxidation than whites, which could result in an unfavorable metabolic profile when exposed to increased high-fat foods consumption and decreased physical activity as in current modern lifestyle. Objective To determine substrate partitioning, liver fat accumulation and metabolic profile in South Asian and white men in response to overfeeding with high-fat diet under sedentary conditions in a respiration chamber. Design Ten South Asian men (BMI, 18-29 kg/m(2)) and 10 white men (BMI, 22-33 kg/m(2)), matched for body fat percentage, aged 20-40 year were included. A weight maintenance diet (30% fat, 55% carbohydrate, and 15% protein) was given for 3 days. Thereafter, a baseline measurement of liver fat content (1H-MRS) and blood parameters was performed. Subsequently, subjects were overfed (150% energy requirement) with a high-fat diet (60% fat, 25% carbohydrate, and 15% protein) over 3 consecutive days while staying in a respiration chamber mimicking a sedentary lifestyle. Energy expenditure and substrate use were measured for 3 x 24-h. Liver fat and blood parameters were measured again after the subjects left the chamber. Results The 24-h fat oxidation as a percentage of total energy expenditure did not differ between ethnicities (P = 0.30). Overfeeding increased liver fat content (P = 0.02), but the increase did not differ between ethnicities (P = 0.64). In South Asians, overfeeding tended to increase LDL-cholesterol (P = 0.08), tended to decrease glucose clearance (P = 0.06) and tended to elevate insulin response (P = 0.07) slightly more than whites. Conclusions Despite a similar substrate partitioning and similar accretion of liver fat, overfeeding with high-fat under sedentary conditions tended to have more adverse effects on the lipid profile and insulin sensitivity in South Asians.

Background A distinct serum metabonomic pattern has been previously revealed to be associated with various forms of liver disease. Here, we aimed to apply mass spectrometry to obtain serum metabolomic profiles from individuals with cholangiocarcinoma and benign hepatobiliary diseases to gain an insight into pathogenesis and search for potential early-disease biomarkers. Methods Serum samples were profiled using a hydrophilic interaction liquid chromatography platform, coupled to a mass spectrometer. A total of 47 serum specimens from 8 cholangiocarcinoma cases, 20 healthy controls, 8 benign disease controls (bile duct strictures) and 11 patients with hepatocellular carcinoma (as malignant disease controls) were included. Data analysis was performed using univariate and multivariate statistics. Results The serum metabolome disparities between the metabolite profiles from healthy controls and patients with hepatobiliary disease were predominantly related to changes in lipid and lipid-derived compounds (phospholipids, bile acids and steroids) and amino acid metabolites (phenylalanine). A metabolic pattern indicative of inflammatory response due to cirrhosis and cholestasis was associated with the disease groups. The abundance of phospholipid metabolites was altered in individuals with liver disease, particularly cholangiocarcinoma, but no significant difference was seen between profiles from patients with benign biliary strictures and cholangiocarcinoma. Conclusion The serum metabolome in cholangiocarcinoma exhibited changes in metabolites related to inflammation, altered energy production and phospholipid metabolism. This study serves to highlight future avenues for biomarker research in large-scale studies.

Migraines constitute a common neurological and headache disorder affecting around 15% of the world’s population. In addition to other mechanisms, neurogenic neuroinflammation has been proposed to play a part in migraine chronification, which includes peripheral and central sensitization. There is therefore considerable evidence suggesting that inflammation in the intracranial meninges could be a key element in addition to calcitonin gene-related peptide (CGRP), leading to sensitization of trigeminal meningeal nociceptors in migraines. There are several studies that have utilized this approach, with a strong focus on using inflammatory animal models. Data from these studies show that the inflammatory process involves sensitization of trigeminovascular afferent nerve terminals. Further, by applying a wide range of different pharmacological interventions, insight has been gained on the pathways involved. Importantly, we discuss how animal models should be used with care and that it is important to evaluate outcomes in the light of migraine pathology.

Nature Communications 13, 2545 (2022). doi:10.1038/s41467-022-30227-5, Published by Nature Publishing Group UK, [London]

Context There is an ongoing debate about whether and how fructose is involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). A recent experimental study showed an increased intrahepatic triglyceride (IHTG) content in mice deficient for aldolase B (aldo B−/−), the enzyme that converts fructose-1-phosphate to triose phosphates. Objective To translate these experimental findings to the human situation. Design Case-control study. Setting Outpatient clinic for inborn errors of metabolism. Patients or Other Participants Patients with hereditary fructose intolerance, a rare inborn error of metabolism caused by a defect in aldolase B (n = 15), and healthy persons matched for age, sex, and body mass index (BMI) (n =15). Main Outcome Measure IHTG content, assessed by proton magnetic resonance spectroscopy. Results IHTG content was higher in aldo B−/− patients than controls (2.5% vs 0.6%; P = 0.001) on a background of lean body mass (median BMI, 20.4 and 21.8 kg/m2, respectively). Glucose excursions during an oral glucose load were higher in aldo B−/− patients (P = 0.043). Hypoglycosylated transferrin, a surrogate marker for hepatic fructose-1-phosphate concentrations, was more abundant in aldo B−/− patients than in controls (P < 0.001). Finally, plasma β-hydroxybutyrate, a biomarker of hepatic β-oxidation, was lower in aldo B−/− patients than controls (P = 0.009). Conclusions This study extends previous experimental findings by demonstrating that aldolase B deficiency also results in IHTG accumulation in humans. It suggests that the accumulation of fructose-1-phosphate and impairment of β-oxidation are involved in the pathogenesis.

N-acetylaspartate (NAA) is synthesized by aspartate N-acetyltransferase (gene: Nat8l) from acetyl–coenzyme A and aspartate. In the brain, NAA is considered an important energy metabolite for lipid synthesis. However, the role of NAA in peripheral tissues remained elusive. Therefore, we characterized the metabolic phenotype of knockout (ko) and adipose tissue–specific (ako) Nat8l-ko mice as well as NAA-supplemented mice on various diets. We identified an important role of NAA availability in the brain during adolescence, as 75% of Nat8l-ko mice died on fat-free diet (FFD) after weaning but could be rescued by NAA supplementation. In adult life, NAA deficiency promotes a beneficial metabolic phenotype, as Nat8l-ko and Nat8l-ako mice showed reduced body weight, increased energy expenditure, and improved glucose tolerance on chow, high-fat, and FFDs. Furthermore, Nat8l-deficient adipocytes exhibited increased mitochondrial respiration, ATP synthesis, and an induction of browning. Conversely, NAA-treated wild-type mice showed reduced adipocyte respiration and lipolysis and increased de novo lipogenesis, culminating in reduced energy expenditure, glucose tolerance, and insulin sensitivity. Mechanistically, our data point to a possible role of NAA as modulator of pancreatic insulin secretion and suggest NAA as a critical energy metabolite for adipocyte and whole-body energy homeostasis.—Hofer, D. C., Zirkovits, G., Pelzmann, H. J., Huber, K., Pessentheiner, A. R., Xia, W., Uno, K., Miyazaki, T., Kon, K., Tsuneki, H., Pendl, T., Al Zoughbi, W., Madreiter-Sokolowski, C. T., Trausinger, G., Abdellatif, M., Schoiswohl, G., Schreiber, R., Eisenberg, T., Magnes, C., Sedej, S., Eckhardt, M., Sasahara, M., Sasaoka, T., Nitta, A., Hoefler, G., Graier, W. F., Kratky, D., Auwerx, J., Bogner-Strauss, J. G. N-acetylaspartate availability is essential for juvenile survival on fat-free diet and determines metabolic health.

Purpose Heating of gradient coils and passive shim components is a common cause of instability in the B0 field, especially when gradient intensive sequences are used. The aim of the study was to set a benchmark for typical drift encountered during MR spectroscopy (MRS) to assess the need for real-time field-frequency locking on MRI scanners by comparing field drift data from a large number of sites. Method A standardized protocol was developed for 80 participating sites using 99 3T MR scanners from 3 major vendors. Phantom water signals were acquired before and after an EPI sequence. The protocol consisted of: minimal preparatory imaging; a short pre-fMRI PRESS; a ten-minute fMRI acquisition; and a long post-fMRI PRESS acquisition. Both pre- and post-fMRI PRESS were non-water suppressed. Real-time frequency stabilization/adjustment was switched off when appropriate. Sixty scanners repeated the protocol for a second dataset. In addition, a three-hour post-fMRI MRS acquisition was performed at one site to observe change of gradient temperature and drift rate. Spectral analysis was performed using MATLAB. Frequency drift in pre-fMRI PRESS data were compared with the first 5:20 minutes and the full 30:00 minutes of data after fMRI. Median (interquartile range) drifts were measured and showed in violin plot. Paired t-tests were performed to compare frequency drift pre- and post-fMRI. A simulated in vivo spectrum was generated using FID-A to visualize the effect of the observed frequency drifts. The simulated spectrum was convolved with the frequency trace for the most extreme cases. Impacts of frequency drifts on NAA and GABA were also simulated as a function of linear drift. Data from the repeated protocol were compared with the corresponding first dataset using Pearson's and intraclass correlation coefficients (ICC). Results Of the data collected from 99 scanners, 4 were excluded due to various reasons. Thus, data from 95 scanners were ultimately analyzed. For the first 5:20 min (64 transients), median (interquartile range) drift was 0.44 (1.29) Hz before fMRI and 0.83 (1.29) Hz after. This increased to 3.15 (4.02) Hz for the full 30 min (360 transients) run. Average drift rates were 0.29 Hz/min before fMRI and 0.43 Hz/min after. Paired t-tests indicated that drift increased after fMRI, as expected (p < 0.05). Simulated spectra convolved with the frequency drift showed that the intensity of the NAA singlet was reduced by up to 26%, 44 % and 18% for GE, Philips and Siemens scanners after fMRI, respectively. ICCs indicated good agreement between datasets acquired on separate days. The single site long acquisition showed drift rate was reduced to 0.03 Hz/min approximately three hours after fMRI. Discussion This study analyzed frequency drift data from 95 3T MRI scanners. Median levels of drift were relatively low (5-min average under 1 Hz), but the most extreme cases suffered from higher levels of drift. The extent of drift varied across scanners which both linear and nonlinear drifts were observed.

Much research has been conducted on sexual differences of the human brain to determine whether and to what extent a brain gender exists. Consequently, a variety of studies using different neuroimaging techniques attempted to identify the existence of a brain phenotype in people with gender dysphoria (GD). However, to date, brain sexual differences at the metabolite level using magnetic resonance spectroscopy (1H-MRS) have not been explored in transgender people. In this study, 28 cisgender men (CM) and 34 cisgender women (CW) and 29 transgender men with GD (TMGD) underwent 1H-MRS at 3 Tesla MRI to characterize common brain metabolites. Specifically, levels of N–acetyl aspartate (NAA), choline (Cho), creatine (Cr), glutamate and glutamine (Glx), and myo-inositol + glycine (mI + Gly) were assessed in two brain regions, the amygdala-anterior hippocampus and the lateral parietal cortex. The results indicated a sex-assigned at birth pattern for Cho/Cr in the amygdala of TMGD. In the parietal cortex, a sex-assigned at birth and an intermediate pattern were found. Though assessed post-hoc, exploration of the age of onset of GD in TMGD demonstrated within-group differences in absolute NAA and relative Cho/Cr levels, suggestive for a possible developmental trend. While brain metabolite levels in TMGD resembled those of CW, some interesting findings, such as modulation of metabolite concentrations by age of onset of GD, warrant future inquiry.

Functional magnetic resonance imaging (fMRI) using the blood oxygenation level-dependent (BOLD) contrast indirectly probes neuronal activity changes via evoked cerebral blood flow (CBF), cerebral blood volume (CBV) and cerebral metabolic rate of oxygen (CMR02) changes. The gradient-echo BOLD signal is mostly sensitive to ascending veins in the tissue and to pial veins. Thereby, the achievable spatial specificity to neuronal activation is limited. Furthermore, the non-linear interaction of CBF, CBV and CMR02 can hamper quantitative interpretations of the BOLD signal across cortical depths with different baseline physiology. Measuring CBF, CBV or CMR02 directly on a depth-dependent level has the potential to overcome these limitations. Here, we review these candidates of physiologically well-defined contrasts with the particular focus on arterial spin labeling (ASL), vascular space occupancy (VASO) and calibrated fMRI. These methods are reviewed with respect to their fMRI sequence parameter space and the applicability for neuroscientific studies in humans. We show representative results of depth-dependent 'non-BOLD-fMRI' in humans and their spatiotemporal characteristics. We conclude that non-BOLD methods are promising alternatives compared to conventional fMRI as they can provide improved spatial specificity, quantifiability and, hence, physiological interpretability as a function of cortical depth. At submillimeter resolution with inherently low signal-to-noise ratio (SNR), however, their use is still challenging. Nevertheless, we believe that 'non-BOLD-fMRI' is a useful alternative for depth-dependent investigations, by providing valuable insights into neurovascular coupling models that facilitate the interpretability of fMRI for neuroscientific applications.

Accurate and reliable quantification of brain metabolites measured in vivo using 1H magnetic resonance spectroscopy (MRS) is a topic of continued interest. Aside from differences in the basic approach to quantification, the quantification of metabolite data acquired at different sites and on different platforms poses an additional methodological challenge. In this study, spectrally edited γ-aminobutyric acid (GABA) MRS data were analyzed and GABA levels were quantified relative to an internal tissue water reference. Data from 284 volunteers scanned across 25 research sites were collected using GABA+ (GABA + co-edited macromolecules (MM)) and MM-suppressed GABA editing. The unsuppressed water signal from the volume of interest was acquired for concentration referencing. Whole-brain T1-weighted structural images were acquired and segmented to determine gray matter, white matter and cerebrospinal fluid voxel tissue fractions. Water-referenced GABA measurements were fully corrected for tissue-dependent signal relaxation and water visibility effects. The cohort-wide coefficient of variation was 17% for the GABA + data and 29% for the MM-suppressed GABA data. The mean within-site coefficient of variation was 10% for the GABA + data and 19% for the MM-suppressed GABA data. Vendor differences contributed 53% to the total variance in the GABA + data, while the remaining variance was attributed to site- (11%) and participant-level (36%) effects. For the MM-suppressed data, 54% of the variance was attributed to site differences, while the remaining 46% was attributed to participant differences. Results from an exploratory analysis suggested that the vendor differences were related to the unsuppressed water signal acquisition. Discounting the observed vendor-specific effects, water-referenced GABA measurements exhibit similar levels of variance to creatine-referenced GABA measurements. It is concluded that quantification using internal tissue water referencing is a viable and reliable method for the quantification of in vivo GABA levels. ispartof: NEUROIMAGE vol:191 pages:537-548 ispartof: location:United States status: published

PURPOSE: Inhomogeneities in the static magnetic field (B0 ) deteriorate MRSI data quality by lowering the spectral resolution and SNR. MRSI with low spatial resolution is also prone to lipid bleeding. These problems are increasingly problematic at ultra-high fields. An approach to tackling these challenges independent of B0 -shim hardware is to increase the spatial resolution. Therefore, we investigated the effect of improved spatial resolution on spectral quality and quantification at 4 field strengths. METHODS: Whole-brain MRSI data was simulated for 3 spatial resolutions and 4 B0 s based on experimentally acquired MRI data and simulated free induction decay signals of metabolites and lipids. To compare the spectral quality and quantification, we derived SNR normalized to the voxel size (nSNR), linewidth and metabolite concentration ratios, their Cramer-Rao-lower-bounds (CRLBs), and the absolute percentage error (APE) of estimated concentrations compared to the gold standard for the whole-brain and 8 brain regions. RESULTS: At 7T, we found up to a 3.4-fold improved nSNR (in the frontal lobe) and a 2.8-fold reduced linewidth (in the temporal lobe) for 1 cm3 versus 0.25 cm3 resolution. This effect was much more pronounced at higher and less homogenous B0 (1.6-fold improved nSNR and 1.8-fold improved linewidth in the parietal lobe at 3T). This had direct implications for quantification: the volume of reliably quantified spectra increased with resolution by 1.2-fold and 1.5-fold (when thresholded by CRLBs or APE, respectively). CONCLUSION: MRSI data quality benefits from increased spatial resolution particularly at higher B0 , and leads to more reliable metabolite quantification. In conjunction with the development of better B0 shimming hardware, this will enable robust whole-brain MRSI at ultra-high field.

PURPOSE: Inhomogeneities in the static magnetic field (B0 ) deteriorate MRSI data quality by lowering the spectral resolution and SNR. MRSI with low spatial resolution is also prone to lipid bleeding. These problems are increasingly problematic at ultra-high fields. An approach to tackling these challenges independent of B0 -shim hardware is to increase the spatial resolution. Therefore, we investigated the effect of improved spatial resolution on spectral quality and quantification at 4 field strengths.METHODS: Whole-brain MRSI data was simulated for 3 spatial resolutions and 4 B0 s based on experimentally acquired MRI data and simulated free induction decay signals of metabolites and lipids. To compare the spectral quality and quantification, we derived SNR normalized to the voxel size (nSNR), linewidth and metabolite concentration ratios, their Cramer-Rao-lower-bounds (CRLBs), and the absolute percentage error (APE) of estimated concentrations compared to the gold standard for the whole-brain and 8 brain regions.RESULTS: At 7T, we found up to a 3.4-fold improved nSNR (in the frontal lobe) and a 2.8-fold reduced linewidth (in the temporal lobe) for 1 cm3 versus 0.25 cm3 resolution. This effect was much more pronounced at higher and less homogenous B0 (1.6-fold improved nSNR and 1.8-fold improved linewidth in the parietal lobe at 3T). This had direct implications for quantification: the volume of reliably quantified spectra increased with resolution by 1.2-fold and 1.5-fold (when thresholded by CRLBs or APE, respectively).CONCLUSION: MRSI data quality benefits from increased spatial resolution particularly at higher B0 , and leads to more reliable metabolite quantification. In conjunction with the development of better B0 shimming hardware, this will enable robust whole-brain MRSI at ultra-high field.

Background: Whole-grain wheat (WGW) is described as nutritionally superior to refined wheat (RW) and thus advocated as the healthy choice, although evidence from intervention studies is often inconsistent. The liver, as the central organ in energy metabolism, might be an important target organ for WGW interventions. Objective: The aim of this study was to investigate the potential benefits of WGW consumption compared with RW consumption on liver health and associated parameters. Design: We performed a double-blind, parallel trial in which 50 overweight 45- to 70-y-old men and postmenopausal women were randomly allocated to a 12-wk intervention with either WGW (98 g/d) or RW (98 g/d) products. Before and after the intervention we assessed intrahepatic triglycerides (IHTGs) and fat distribution by proton magnetic resonance spectroscopy/magnetic resonance imaging, fecal microbiota composition, adipose tissue gene expression, and several fasting plasma parameters, as well as postprandial plasma lipids after a mixed meal. Results: Fasting plasma cholesterol, triglycerides, nonesterified fatty acids, and insulin were not affected by RW or WGW intervention. We observed a substantial increase of 49.1% in IHTGs in the RW when compared with the WGW group (P = 0.033). Baseline microbiota composition could not predict the increase in IHTGs after RW, but gut microbiota diversity decreased in the RW group when compared with the WGW group (P = 0.010). In the WGW group, we observed increased postprandial triglyceride levels compared with the RW group (P = 0.020). In addition, the WGW intervention resulted in a trend towards lower fasting levels of the liver acute-phase proteins serum amyloid A (P = 0.057) and C-reactive protein (P = 0.064) when compared to the RW intervention. Conclusions: A 12-wk RW intervention increases liver fat and might contribute to the development of nonalcoholic fatty liver disease, whereas a 12-wk 98-g/d WGW intervention prevents a substantial increase in liver fat. Our results show that incorporating feasible doses of WGW in the diet at the expense of RW maintains liver health. The study was registered at clinicaltrials.gov as NCT02385149.

Modern radiation therapy is delivered with great precision, in part by relying on high-resolution multidimensional anatomic imaging to define targets in space and time. The development of quantitative imaging (QI) modalities capable of monitoring biologic parameters could provide deeper insight into tumor biology and facilitate more personalized clinical decision-making. The Quantitative Imaging Network (QIN) was established by the National Cancer Institute to advance and validate these QI modalities in the context of oncology clinical trials. In particular, the QIN has significant interest in the application of QI to widen the therapeutic window of radiation therapy. QI modalities have great promise in radiation oncology and will help address significant clinical needs, including finer prognostication, more specific target delineation, reduction of normal tissue toxicity, identification of radioresistant disease, and clearer interpretation of treatment response. Patient-specific QI is being incorporated into radiation treatment design in ways such as dose escalation and adaptive replanning, with the intent of improving outcomes while lessening treatment morbidities. This review discusses the current vision of the QIN, current areas of investigation, and how the QIN hopes to enhance the integration of QI into the practice of radiation oncology. (C) 2018 Elsevier Inc. All rights reserved.

Modern radiation therapy is delivered with great precision, in part by relying on high-resolution multi-dimensional anatomical imaging to define targets in space and time. The development of quantitative imaging (QI) modalities capable of monitoring biologic parameters has the potential to provide deeper insight into tumor biology and facilitate more personalized clinical decision-making. The Quantitative Imaging Network (QIN) was established by the National Cancer Institute (NCI) to advance and validate these QI modalities in the context of oncology clinical trials, emphasizing the great clinical need for this technology. In particular, the QIN has significant interest in the application of QI to widen the therapeutic window of radiation therapy. QI modalities have great promise in radiation oncology and will help address significant clinical needs including finer prognostication, more specific target delineation, reduction of normal tissue toxicity, identification of radioresistant disease, and clearer interpretation of treatment response. Patient-specific quantitative information is being incorporated into radiation treatment design in ways such as dose escalation and adaptive replanning, with the intent of improving outcomes while lessening treatment morbidities. This review discusses the current vision of the QIN, current areas of investigation, and how it hopes to enhance the integration of QI into the practice of radiation oncology.

BACKGROUND AND PURPOSE: The secondary progressive phase of multiple sclerosis is characterised by disability progression due to processes that lead to neurodegeneration. Surrogate markers such as those derived from MRI are beneficial in understanding the pathophysiology that drives disease progression and its relationship to clinical disability. We undertook a 1H-MRS imaging study in a large secondary progressive MS (SPMS) cohort, to examine whether metabolic markers of brain injury are associated with measures of disability, both physical and cognitive. MATERIALS AND METHODS: A cross-sectional analysis of individuals with secondary-progressive MS was performed in 119 participants. They underwent 1H-MR spectroscopy to obtain estimated concentrations and ratios to total Cr for total NAA, mIns, Glx, and total Cho in normal-appearing WM and GM. Clinical outcome measures chosen were the following: Paced Auditory Serial Addition Test, Symbol Digit Modalities Test, Nine-Hole Peg Test, Timed 25-foot Walk Test, and the Expanded Disability Status Scale. The relationship between these neurometabolites and clinical disability measures was initially examined using Spearman rank correlations. Significant associations were then further analyzed in multiple regression models adjusting for age, sex, disease duration, T2 lesion load, normalized brain volume, and occurrence of relapses in 2 years preceding study entry. RESULTS: Significant associations, which were then confirmed by multiple linear regression, were found in normal-appearing WM for total NAA (tNAA)/total Cr (tCr) and the Nine-Hole Peg Test (r = 0.23; 95% CI, 0.06-0.40); tNAA and tNAA/tCr and the Paced Auditory Serial Addition Test (r = 0.21; 95% CI, 0.03-0.38) (r = 0.19; 95% CI, 0.01-0.36); mIns/tCr and the Paced Auditory Serial Addition Test, (r = -0.23; 95% CI, -0.39 to -0.05); and in GM for tCho and the Paced Auditory Serial Addition Test (r = -0.24; 95% CI, -0.40 to -0.06). No other GM or normal-appearing WM relationships were found with any metabolite, with associations found during initial correlation testing losing significance after multiple linear regression analysis. CONCLUSIONS: This study suggests that metabolic markers of neuroaxonal integrity and astrogliosis in normal-appearing WM and membrane turnover in GM may act as markers of disability in secondary-progressive MS.

With a 40‐year history of use for in vivo studies, the terminology used to describe the methodology and results of magnetic resonance spectroscopy (MRS) has grown substantially and is not consistent in many aspects. Given the platform offered by this special issue on advanced MRS methodology, the authors decided to describe many of the implicated terms, to pinpoint differences in their meanings and to suggest specific uses or definitions. This work covers terms used to describe all aspects of MRS, starting from the description of the MR signal and its theoretical basis to acquisition methods, processing and to quantification procedures, as well as terms involved in describing results, for example, those used with regard to aspects of quality, reproducibility or indications of error. The descriptions of the meanings of such terms emerge from the descriptions of the basic concepts involved in MRS methods and examinations. This paper also includes specific suggestions for future use of terms where multiple conventions have emerged or coexisted in the past., This work defines terms and explains concepts used to describe all aspects of MR spectroscopy, starting from the definition of the MR signal and its theoretical basis to acquisition methods, processing and quantification procedures, as well as terms involved in describing results, including quality aspects, reproducibility or indications of error. Also featured are specific suggestions for future use of terms where multiple conventions have emerged or previously coexisted.

With a worldwide incidence of 15 million cases, preterm birth is a major contributor to neonatal mortality and morbidity, and concomitant social and economic burden Preterm infants are predisposed to life-long neurological disorders due to the immaturity of the brain. The risks are inversely proportional to maturity at birth. In the majority of extremely preterm infants (

Previous research in young adults has demonstrated that both motor learning and transcranial direct current stimulation (tDCS) trigger decreases in the levels of gamma‐aminobutyric acid (GABA) in the sensorimotor cortex, and these decreases are linked to greater learning. Less is known about the role of GABA in motor learning in healthy older adults, a knowledge gap that is surprising given the established aging‐related reductions in sensorimotor GABA. Here, we examined the effects of motor learning and subsequent tDCS on sensorimotor GABA levels and resting‐state functional connectivity in the brains of healthy older participants. Thirty‐six older men and women completed a motor sequence learning task before receiving anodal or sham tDCS to the sensorimotor cortex. GABA‐edited magnetic resonance spectroscopy of the sensorimotor cortex and resting‐state (RS) functional magnetic resonance imaging data were acquired before and after learning/stimulation. At the group level, neither learning nor anodal tDCS significantly modulated GABA levels or RS connectivity among task‐relevant regions. However, changes in GABA levels from the baseline to post‐learning session were significantly related to motor learning magnitude, age, and baseline GABA. Moreover, the change in functional connectivity between task‐relevant regions, including bilateral motor cortices, was correlated with baseline GABA levels. These data collectively indicate that motor learning‐related decreases in sensorimotor GABA levels and increases in functional connectivity are limited to those older adults with higher baseline GABA levels and who learn the most. Post‐learning tDCS exerted no influence on GABA levels, functional connectivity or the relationships among these variables in older adults., Gamma‐aminobutyric acid (GABA)‐edited magnetic resonance spectroscopy of the sensorimotor cortex and resting‐state (RS) functional magnetic resonance imaging data were acquired before and after a motor learning task and either anodal or sham transcranial direct current stimulation (tDCS). Results demonstrated that neither motor sequence learning nor subsequent tDCS significantly modulated GABA+ levels or RS functional connectivity at the group level in older adults. However, individual differences in the learning‐related modulations in GABA+ levels were associated with the participants' age, baseline GABA+ levels, and the magnitude of learning. Higher baseline GABA was also linked to a learning‐related increase in RS functional connectivity between motor task‐relevant regions, including bilateral motor cortices.

Diffusion Magnetic Resonance Imaging (dMRI) is one of the most important contemporary non-invasive modalities for probing tissue structure at the microscopic scale. The majority of dMRI techniques employ standard single diffusion encoding (SDE) measurements, covering different sequence parameter ranges depending on the complexity of the method. Although many signal representations and biophysical models have been proposed for SDE data, they are intrinsically limited by a lack of specificity. Advanced dMRI methods have been proposed to provide additional microstructural information beyond what can be inferred from SDE. These enhanced contrasts can play important roles in characterizing biological tissues, for instance upon diseases (e.g. neurodegenerative, cancer, stroke), aging, learning, and development. In this review we focus on double diffusion encoding (DDE), which stands out among other advanced acquisitions for its versatility, ability to probe more specific diffusion correlations, and feasibility for preclinical and clinical applications. Various DDE methodologies have been employed to probe compartment sizes (Section 3), decouple the effects of microscopic diffusion anisotropy from orientation dispersion (Section 4), probe displacement correlations, study exchange, or suppress fast diffusing compartments (Section 6). DDE measurements can also be used to improve the robustness of biophysical models (Section 5) and study intra-cellular diffusion via magnetic resonance spectroscopy of metabolites (Section 7). This review discusses all these topics as well as important practical aspects related to the implementation and contrast in preclinical and clinical settings (Section 9) and aims to provide the readers a guide for deciding on the right DDE acquisition for their specific application.

International audience; Background & Aims: Dietary changes can modulate gut microbiota and interact with cirrhosis. Our prior study demonstrated that microbial diversity was higher in Turkish versus USA cirrhotics, which was associated with lower risk of 90-day hospitalizations. We aimed to define gut microbial functional and metabolomic changes to increase insight into benefits of the Mediterranean compared to Western diets.Methods: In all, 139 Turkish (46 controls/50 compensated/43 decompensated) and 157 American subjects (48 controls/59 compensated/50 decompensated) were studied. Turkish subjects consumed a modified Mediterranean diet with daily fermented milk intake, whereas Americans consumed a Western diet. Predicted gut microbial functionalities and plasma metabolomics were compared between/within countries. Correlation network differences between microbiota and metabolites in cirrhotics from Turkey vs the USA were evaluated.Results: Predicted microbial function showed lower amino acid, bioenergetics and lipid pathways, with functions related to vitamin B, glycan, xenobiotic metabolism, DNA/RNA synthesis, in cirrhotics from Turkey compared to the USA. Plasma metabolomics demonstrated higher relative lactate levels in Turkey vs the USA. The metabolite changes in decompensated cirrhosis, compared to controls, showed similar trends in Turkey and the USA, with reduced lipids and phosphocholines. Phosphocholines were significantly lower in patients hospitalized in 90 days (P = .03). Correlation networks in cirrhotics demonstrated linkage differences between beneficial taxa, Blautia and Oscillispira, and lactate and unsaturated lipids, in Turkey compared to American patients.Conclusions: A modified Mediterranean diet was associated with altered plasma metabolomics and beneficially alters microbiota functionality and correlations compared to Western diet in cirrhosis. These altered diet-microbial interactions could potentially affect the 90-day hospitalization risk.

The neurobiological mechanisms underlying the association between cannabis use and acute or long-lasting psychosis are not completely understood. While some evidence suggests altered striatal dopamine may underlie the association, direct evidence that cannabis use affects either acute or chronic striatal dopamine is inconclusive. In contrast, pre-clinical research suggests that cannabis may affect dopamine via modulation of glutamate signaling. A double-blind, randomized, placebo-controlled, crossover design was used to investigate whether altered striatal glutamate, as measured using proton magnetic resonance spectroscopy, underlies the acute psychotomimetic effects of intravenously administered delta-9-tetrahydrocannabinol (Δ9-THC; 1.19 mg/2 ml), the key psychoactive ingredient in cannabis, in a set of 16 healthy participants (7 males) with modest previous cannabis exposure. Compared to placebo, acute administration of Δ9-THC significantly increased Glutamate (Glu) + Glutamine (Gln) metabolites (Glx) in the left caudate head (P = 0.027). Furthermore, compared to individuals who were not sensitive to the psychotomimetic effects of Δ9-THC, individuals who developed transient psychotic-like symptoms (~70% of the sample) had significantly lower baseline Glx (placebo; P 7= 0.023) and a 2.27-times higher increase following Δ9-THC administration. Lower baseline Glx values (r = -0.55; P = 0.026) and higher previous cannabis exposure (r = 0.52; P = 0.040) were associated with a higher Δ9-THC-induced Glx increase. These results suggest that an increase in striatal glutamate levels may underlie acute cannabis-induced psychosis while lower baseline levels may be a marker of greater sensitivity to its acute psychotomimetic effects and may have important public health implications. ispartof: MOLECULAR PSYCHIATRY vol:25 issue:12 pages:3231-3240 ispartof: location:England status: published

Cannabis is the most commonly used illicit drug in the world. However, because of a changing legal landscape and rising interest in therapeutic utility, there is an increasing trend in (long‐term) use and possibly cannabis impairment. Importantly, a growing body of evidence suggests that regular cannabis users develop tolerance to the impairing, as well as the rewarding, effects of the drug. However, the neuroadaptations that may underlie cannabis tolerance remain unclear. Therefore, this double‐blind, randomized, placebo‐controlled, cross‐over study assessed the acute influence of cannabis on the brain and behavioral outcomes in two distinct cannabis user groups. Twelve occasional and 12 chronic cannabis users received acute doses of cannabis (300‐μg/kg delta‐9‐tetrahydrocannabinol) and placebo and underwent ultrahigh field functional magnetic resonance imaging and magnetic resonance spectroscopy. In occasional users, cannabis induced significant neurometabolic alterations in reward circuitry, namely, decrements in functional connectivity and increments in striatal glutamate concentrations, which were associated with increases in subjective high and decreases in performance on a sustained attention task. Such changes were absent in chronic users. The finding that cannabis altered circuitry and distorted behavior in occasional, but not chronic users, suggests reduced responsiveness of the reward circuitry to cannabis intoxication in chronic users. Taken together, the results suggest a pharmacodynamic mechanism for the development of tolerance to cannabis impairment, of which is important to understand in the context of the long‐term therapeutic use of cannabis‐based medications, as well as in the context of public health and safety of cannabis use when performing day‐to‐day operations., Using an ultra‐high field multimodal brain imaging approach, we showed that in occasional cannabis users, acute THC administration increased striatal glutamate and decreased functional connectivity in the reward system, which were associated with increases in subjective high and decreases in sustained attention. Such changes were absent in chronic cannabis users. Findings suggest the development of neuroadaptations in reward circuitry after excessive use of cannabis, which may underlie behavioral tolerance to the drug.

In the past, different types of diet with a generally low-carbohydrate content (

Ongoing treatments for genetic developmental disorders of the central nervous system are mostly symptomatic and do not correct the genetic cause. Recent identification of common mechanisms between diseases has suggested that new therapeutic targets could be applied across intellectual disabilities with potential disease-modifying properties. The European Down syndrome and other genetic developmental disorders (DSG2D) network joined basic and clinical scientists to foster this research and carry out clinical trials. Here we discuss common mechanisms between several intellectual disabilities from genetic origin including Down's and Fragile X syndromes: i) how to model these complex diseases using neuronal cells and brain organoids derived from induced pluripotent stem cells; ii) how to integrate genomic, proteomic and interactome data to help defining common mechanisms and boundaries between diseases; iii) how to target common pathways for designing clinical trials and assessing their efficacy; iv) how to bring new neuro-therapies, such as noninvasive brain stimulations and cognitive training to clinical research. The basic and translational research efforts of the last years have utterly transformed our understanding of the molecular pathology of these diseases but much is left to be done to bring them to newborn babies and children to improve their quality of life.

Hereditary galactosemia is an inborn error of carbohydrate metabolism. Galactose is metabolized by Leloir pathway enzymes; galactokinase (GALK), galactose-1-phosphate uridylyltransferase (GALT) and UDP-galactose 4-epimerase (GALE). The defects in these enzymes cause galactosemia in an autosomal recessive manner. The severe GALT deficiency, or classic galactosemia, is life-threatening in the newborn period. The treatment for classic galactosemia is dietary restriction of lactose. Although implementation of lactose restricted diet is efficient in resolving the acute complications, it is not sufficient to prevent long-term complications affecting the brain and female gonads, the two main target organs of damage. Implementation of molecular genetics diagnostic tools and GALT enzyme assays are instrumental in distinguishing classic galactosemia from clinical and biochemical variant forms of GALT deficiency. Better understanding of mechanisms responsible for the phenotypic variation even within the same genotype is essential to provide appropriate counseling for families. Utilization of a lactose restricted diet is also recommended for GALK deficiency and some rare forms of GALE deficiency. Novel modes of therapies are being explored; they may be beneficial if access issues to the affected tissues are circumvented and optimum use of therapeutic window is achieved. (C) 2018 Elsevier Inc. All rights reserved.

Purpose While PRESS is often employed to measure glutamate concentrations, MEGA-PRESS enables simultaneous Glx (glutamate and glutamine) and GABA measurements. This study aimed to compare validation, repeatability, and concordance of different approaches for glutamate quantification at 3 T to aid future studies in their selection of the appropriate sequence and quantification method. Materials and methods Nine phantoms with different glutamate and glutamine concentrations and five healthy participants were scanned twice to assess respectively the validation and repeatability of measurements with PRESS and MEGA-PRESS. To assess concordance between the different methods, results from 95 human participants were compared. PRESS, MEGA-PRESS (i.e. difference), and the MEGA-PRESS OFF spectra were analyzed with both LCModel and Gannet. Results In vitro, excellent agreement was shown between actual and measured glutamate concentrations for all measurements (r > 0.98). In vivo CVs were better for PRESS (2.9%) than MEGA-PRESS (4.9%) and MEGA-PRESS OFF (4.2%). However, the concordance between the sequences was low (PRESS and MEGA-PRESS OFF, r = 0.3) to modest (MEGA-PRESS versus MEGA-PRESS OFF, r = 0.8). Conclusion Both PRESS and MEGA-PRESS can be employed to measure in vivo glutamate concentrations, although PRESS shows a better repeatability. Comparisons between in vivo glutamate measures of different sequences however need to be interpreted cautiously.

Aims: To examine the distribution of liver fat (LFAT) in non-diabetic subjects and test whether the fat in the right as compared to the left lobe correlates better with components of the metabolic syndrome or not. Methods: In this cross sectional study, we determined LFAT by H-1-MRS in the right lobe (LFAT%(MRS)), and by MRI (LFAT%(MRI)) in four regions of interest (ROIs 1-4, two in the right and two in the left lobe) in 97 non-diabetic subjects (age range 22-74 years, BMI 18-41 kg/m(2)) and compared the accuracy of LFAT(MRI) in the different ROIs in diagnosing non-alcoholic fatty liver disease (NAFLD) using areas under the receiver operator characteristic (AUROC) curves. Results: 38% of the subjects had NAFLD (LFAT%(MRS)). LFAT%(MRI) was significantly higher in the right (5.7 +/- 0.5%) than the left (5.1 +/- 0.4%) lobe (p

Exercise training reduces intrahepatic lipid (IHL) content in people with elevated liver fat content. It is unclear, however, whether exercise training reduces IHL content in people with normal liver fat content. Here, we measured the effect of exercise training on IHL content in people with and people without nonalcohol fatty liver. We further measured changes in insulin sensitivity and hepatic energy metabolism. Eleven males with nonalcoholic fatty liver (NAFL) and 11 body mass index-matched individuals without nonalcoholic fatty liver (CON) completed a 12-wk supervised exercise training program. IHL content (proton magnetic resonance spectroscopy), maximal oxidative capacity (V̇o2max, spiroergometry), total muscle strength, body composition, insulin sensitivity (hyperinsulinemic-euglycemic clamp), hepatic ATP-to-total phosphorus ratio, and the hepatic phosphomonoester-to-phosphodiester (PME/PDE) ratio (phosphorus magnetic resonance spectroscopy) were determined. IHL content reduced with exercise training ( P = 0.014) in the whole study population. The relative reduction in IHL content was comparable in NAFL (−34.5 ± 54.0%) and CON (−28.3 ± 60.1%) individuals ( P = 0.800). V̇o2max ( P < 0.001), total muscle strength ( P < 0.001), and skeletal muscle insulin sensitivity ( P = 0.004) increased, whereas adipose tissue ( P = 0.246) and hepatic ( P = 0.086) insulin sensitivity did not increase significantly. Hepatic ATP-to-total phosphorus ratio ( P = 0.987) and PME/PDE ratio ( P = 0.792) did not change. Changes in IHL content correlated with changes in body weight ( r = 0.451, P = 0.035) and changes in hepatic PME/PDE ratio ( r = 0.569, P = 0.019). In conclusion, exercise training reduced intrahepatic lipid content in people with nonalcoholic fatty liver and in people with normal intrahepatic lipid content, and the percent reduction in intrahepatic lipid content was similar in both groups.

In this review, current imaging techniques and their future perspectives in the field of cardiac metabolic imaging in humans are discussed. This includes a range of noninvasive imaging techniques, allowing a detailed investigation of cardiac metabolism in health and disease. The main imaging modalities discussed are magnetic resonance spectroscopy techniques for determination of metabolite content (triglycerides, glucose, ATP, phosphocreatine, and so on), MRI for myocardial perfusion, and single-photon emission computed tomography and positron emission tomography for quantitation of perfusion and substrate uptake.

In this review, current imaging techniques and their future perspectives in the field of cardiac metabolic imaging in humans are discussed. This includes a range of noninvasive imaging techniques, allowing a detailed investigation of cardiac metabolism in health and disease. The main imaging modalities discussed are magnetic resonance spectroscopy techniques for determination of metabolite content (triglycerides, glucose, ATP, phosphocreatine, and so on), MRI for myocardial perfusion, and single-photon emission computed tomography and positron emission tomography for quantitation of perfusion and substrate uptake.