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Context Adipose tissue (AT) inflammation predisposes to insulin resistance and metabolic syndrome in obesity. Objective To investigate the association between adipocyte size, AT inflammation, systemic inflammation, and metabolic and atherosclerotic complications of obesity in a sex-specific manner. Design Cross-sectional cohort study. Setting University hospital in the Netherlands. Participants A total of 302 adult subjects with a body mass index (BMI) ≥ 27 kg/m2. Main outcome measures We obtained subcutaneous abdominal fat biopsies and systematically assessed, in a sex-specific manner, associations of several parameters of AT inflammation (including adipocyte size, macrophage content, crown-like structures, and gene expression) to biomarkers of systemic inflammation, leukocyte number and function, and to the presence of metabolic syndrome, insulin resistance, and carotid atherosclerotic plaques, assessed with ultrasound. Results Adipocyte size was associated with metabolic syndrome and AT macrophage content with insulin resistance. In contrast, none of the AT parameters was associated with carotid atherosclerosis, although mRNA expression of the anti-inflammatory IL-37 was associated with a lower intima-media thickness. We revealed profound sex-specific differences, with an association between BMI and adipocyte size, and between adipocyte size and metabolic syndrome in men only. Also, only men showed an association between adipocyte size, AT expression of leptin and MCP-1, and AT macrophage numbers, and between AT inflammation (crown-like structure number) and several circulating inflammatory proteins, including high specificity C-reactive protein, and IL-6. Conclusions Inflammation in abdominal subcutaneous adipose tissue is more related to the metabolic than the atherosclerotic complications of obesity, and there are profound sex-specific differences in the association between BMI, adipocyte size, AT inflammation, and systemic inflammation, which are much stronger in men than women.

Contains fulltext : 229584.pdf (Publisher’s version ) (Open Access) Sjögren-Larsson syndrome (SLS) is a rare neurometabolic syndrome caused by deficient fatty aldehyde dehydrogenase. Patients exhibit intellectual disability, spastic paraplegia, and ichthyosis. The accumulation of fatty alcohols and fatty aldehydes has been demonstrated in plasma and skin but never in brain. Brain magnetic resonance imaging and spectroscopy studies, however, have shown an abundant lipid peak in the white matter of patients with SLS, suggesting lipid accumulation in the brain as well. Using histopathology, mass spectrometry imaging, and lipidomics, we studied the morphology and the lipidome of a postmortem brain of a 65-year-old female patient with genetically confirmed SLS and compared the results with a matched control brain. Histopathological analyses revealed structural white matter abnormalities with the presence of small lipid droplets, deficient myelin, and astrogliosis. Biochemically, severely disturbed lipid profiles were found in both white and gray matter of the SLS brain, with accumulation of fatty alcohols and ether lipids. Particularly, long-chain unsaturated ether lipid species accumulated, most prominently in white matter. Also, there was a striking accumulation of odd-chain fatty alcohols and odd-chain ether(phospho)lipids. Our results suggest that the central nervous system involvement in SLS is caused by the accumulation of fatty alcohols leading to a disbalance between ether lipid and glycero(phospho)lipid metabolism resulting in a profoundly disrupted brain lipidome. Our data show that SLS is not a pure leukoencephalopathy, but also a gray matter disease. Additionally, the histopathological abnormalities suggest that astrocytes and microglia might play a pivotal role in the underlying disease mechanism, possibly contributing to the impairment of myelin maintenance.

IntroductionImpaired awareness of hypoglycemia, clinically reflected by the inability to timely detect hypoglycemia, affects approximately 25% of the people with type 1 diabetes. Both altered brain lactate handling and increased cerebral blood flow (CBF) during hypoglycemia appear to be involved in the pathogenesis of impaired awareness of hypoglycemia. Here we examine the effect of lactate on CBF during hypoglycemia.Research design and methodsNine people with type 1 diabetes and normal awareness of hypoglycemia underwent two hyperinsulinemic euglycemic-hypoglycemic (3.0 mmol/L) glucose clamps in a 3T MR system, once with sodium lactate infusion and once with sodium chloride infusion. Global and regional changes in CBF were determined using pseudocontinuous arterial spin labeling.ResultsLactate (3.3±0.6 vs 0.9±0.2 mmol/L during lactate infusion vs placebo infusion, respectively) suppressed the counter-regulatory hormone responses to hypoglycemia. Global CBF increased considerably in response to intravenous lactate infusion but did not further increase during hypoglycemia. Lactate also blunted the hypoglycemia-induced regional redistribution of CBF towards the thalamus.ConclusionsElevated lactate levels enhance global CBF and blunt the thalamic CBF response during hypoglycemia in patients with type 1 diabetes, mimicking observations of impaired awareness of hypoglycemia. These findings suggest that alteration of CBF associated with lactate may play a role in some aspects of the development of impaired awareness of hypoglycemia.Trial registration numberNCT03730909.

Context Subcutaneous adipose tissue (SAT) is not homogeneous, as the fascia scarpa separates the deep SAT (dSAT) from the superficial SAT (sSAT). Objective The aim of this study is to evaluate the sex-specific associations of sSAT and dSAT with hepatic steatosis and metabolic syndrome in overweight individuals. Methods We recruited 285 individuals with a body mass index (BMI) greater than or equal to 27 and aged 55 to 81 years. Abdominal magnetic resonance imaging was performed around level L4 to L5 to measure visceral adipose tissue (VAT), dSAT, and sSAT volumes. The amount of hepatic fat was quantified by MR spectroscopy. Results Men had significantly higher volumes of VAT (122.6 cm3 vs 98.7 cm3, P Conclusion In men, dSAT is associated with hepatic steatosis and adverse metabolic traits, such as lower HDL cholesterol levels, whereas in women with obesity sSAT shows a beneficial relation with respect to hepatic fat content.

Since altered brain lactate handling has been implicated in the development of impaired awareness of hypoglycemia (IAH) in type 1 diabetes, the capacity to transport lactate into the brain during hypoglycemia may be relevant in its pathogenesis. High-intensity interval training (HIIT) increases plasma lactate levels. We compared the effect of HIIT-induced hyperlacticacidemia on brain lactate during hypoglycemia between 1) patients with type 1 diabetes and IAH, 2) patients with type 1 diabetes and normal awareness of hypoglycemia, and 3) healthy participants without diabetes (n = 6 per group). All participants underwent a hypoglycemic (2.8 mmol/L) clamp after performing a bout of HIIT on a cycle ergometer. Before HIIT (baseline) and during hypoglycemia, brain lactate levels were determined continuously with J-difference–editing 1H-MRS, and time curves were analyzed using nonlinear mixed-effects modeling. At the beginning of hypoglycemia (after HIIT), brain lactate levels were elevated in all groups but most pronounced in patients with IAH. During hypoglycemia, brain lactate decreased ∼30% below baseline in patients with IAH but returned to baseline levels and remained there in the other two groups. Our results support the concept of enhanced lactate transport as well as increased lactate oxidation in patients with type 1 diabetes and IAH.

Introduction Non-alcoholic fatty liver disease (NAFLD) is becoming a major health problem worldwide. Inflammation plays an important role in disease pathogenesis and recent studies have shown a potential role for the neutrophil serine proteases (NSPs) proteinase-3 (PR3) and neutrophil elastase (NE) in NAFLD as well as an imbalance between NSPs and their natural inhibitor alpha-1 antitrypsin (AAT). The aim of this study was to investigate whether PR3 and NE plasma concentrations are associated with NAFLD and/or type 2 diabetes. Methods To explore this hypothesis we used several cohorts: a cohort of 271 obese individuals with liver steatosis, a cohort of 41 patients with biopsy-proven NAFLD, a cohort of 401 obese type 2 diabetes patients and a cohort of 205 lean healthy controls; and measured PR3 and NE plasma concentrations. In addition, we measured AAT plasma concentrations in order to investigate if the ratios between NSPs and their natural inhibitor were altered in NAFLD and type 2 diabetes when compared to healthy controls. Results Our data shows an increase in PR3 and NE concentrations and a decrease in AAT concentrations in obese patients when compared to controls. Moreover, PR3 plasma concentrations are increased in patients with liver steatosis. Furthermore, PR3 and NE concentrations in the liver are associated with the advanced stages of NAFLD characterized by NASH and/ or liver fibrosis. Additionally, PR3 and NE concentrations were up-regulated in patients with type 2 diabetes when compared to lean and obese controls. Conclusion We conclude that circulating levels of NSPs associate with obesity-related metabolic disorders. Further research is needed to clearly establish the role of these proteases and investigate whether they could be used as non-invasive markers for NAFLD and/or type 2 diabetes. Electronic supplementary material The online version of this article (10.1186/s10020-019-0084-3) contains supplementary material, which is available to authorized users.

Contains fulltext : 208797.pdf (Publisher’s version ) (Open Access) Administration of lactate during hypoglycemia suppresses symptoms and counterregulatory responses, as seen in patients with type 1 diabetes and impaired awareness of hypoglycemia (IAH), presumably because lactate can substitute for glucose as a brain fuel. Here, we examined whether lactate administration, in a dose sufficient to impair awareness of hypoglycemia, affects brain lactate levels in patients with normal awareness of hypoglycemia (NAH). Patients with NAH (n = 6) underwent two euglycemic-hypoglycemic clamps (2.8 mmol/L), once with sodium lactate infusion (NAH w|lac) and once with saline infusion (NAH w|placebo). Results were compared to those obtained during lactate administration in patients with IAH (n = 7) (IAH w|lac). Brain lactate levels were determined continuously with J-difference editing (1)H-MRS. During lactate infusion, symptom and adrenaline responses to hypoglycemia were considerably suppressed in NAH. Infusion of lactate increased brain lactate levels modestly, but comparably, in both groups (mean increase in NAH w|lac: 0.12 +/- 0.05 micromol/g and in IAH w|lac: 0.06 +/- 0.04 micromol/g). The modest increase in brain lactate may suggest that the excess of lactate is immediately metabolized by the brain, which in turn may explain the suppressive effects of lactate on awareness of hypoglycemia observed in patients with NAH.

Aims/hypothesis Chronic hyperglycaemia in type 1 diabetes affects the structure and functioning of the brain, but the impact of recurrent hypoglycaemia is unclear. Changes in the neurochemical profile have been linked to loss of neuronal function. We therefore aimed to investigate the impact of type 1 diabetes and burden of hypoglycaemia on brain metabolite levels, in which we assumed the burden to be high in individuals with impaired awareness of hypoglycaemia (IAH) and low in those with normal awareness of hypoglycaemia (NAH). Methods We investigated 13 non-diabetic control participants, 18 individuals with type 1 diabetes and NAH and 13 individuals with type 1 diabetes and IAH. Brain metabolite levels were determined by analysing previously obtained 1H magnetic resonance spectroscopy data, measured under hyperinsulinaemic–euglycaemic conditions. Results Brain glutamate levels were higher in participants with diabetes, both with NAH (+15%, p = 0.013) and with IAH (+19%, p = 0.003), compared with control participants. Cerebral glutamate levels correlated with HbA1c levels (r = 0.40; p = 0.03) and correlated inversely (r = −0.36; p = 0.04) with the age at diagnosis of diabetes. Other metabolite levels did not differ between groups, apart from an increase in aspartate in IAH. Conclusions/interpretation In conclusion, brain glutamate levels are elevated in people with type 1 diabetes and correlate with glycaemic control and age of disease diagnosis, but not with burden of hypoglycaemia as reflected by IAH. This suggests a potential role for glutamate as an early marker of hyperglycaemia-induced cerebral complications of type 1 diabetes. ClinicalTrials.gov NCT03286816; NCT02146404; NCT02308293

Contains fulltext : 171319.pdf (Publisher’s version ) (Closed access) Patients on home parenteral nutrition are at risk for developing liver dysfunction, which is due partly to the accumulation of lipids in the liver (steatosis) and may progress to end-stage liver disease with overt liver failure. Therefore, a timely diagnosis with easy access to repeated assessment of the degree of liver steatosis is of great importance. A pilot study was performed in 14 patients on long-term home parenteral nutrition using the computer-aided ultrasound method. Ultrasound radio frequency data were acquired using a phased array transducer and were converted into conventional B-mode images. All patients were subjected to proton magnetic resonance spectroscopy measurement of liver fat content for reference. Computer-aided ultrasound parameters similar to those in a previous validation study in cows revealed significant correlations with fat content measured by magnetic resonance spectroscopy. The most significant parameters were the residual attenuation coefficient (R = 0.95, p < 0.001) and the lateral speckle size (R = 0.77, p = 0.021). These findings indicate the potential usefulness of computer-aided ultrasound for staging of hepatic steatosis.

Contains fulltext : 193245.pdf (Author’s version postprint ) (Open Access) BACKGROUND: Intestinal failure-associated liver disease is a frequent complication in patients with chronic intestinal failure (CIF), with steatosis as a dominant feature in adults. Proton magnetic resonance spectroscopy (1H-MRS) is a noninvasive method to quantify liver fat content (LFC). In this study, LFC was assessed with 1H-MRS, taking into account the possible accumulation of paramagnetic components of home parenteral nutrition (HPN) that may disturb these measurements. METHODS: LFC was measured in 15 adult CIF patients who had been receiving HPN for >6 months. 1H-MR spectra were obtained with a 3 Tesla magnetic resonance (MR) system, with a method correcting for the presence of paramagnetic ions. Patients with low (/=5%, steatosis) LFC were compared with nonparametric statistical tests. RESULTS: 1H-MRS analysis revealed steatosis in 5 patients (median, 10.3%), while 10 patients had normal LFC (median, 0.9%). In all patients, the 1H-MRS results indicated the presence of various amounts of paramagnetic constituents in the liver. Patients with steatosis had higher alanine aminotransferase values than patients without steatosis (median, 60 vs 28 U/L). Unexpectedly, in the steatosis group, the frequency of HPN use was lower, with significant lower total HPN and carbohydrate calories. In 1 patient, MR spectra were of inferior quality, with broadened resonances after infusion with a ferric compound. CONCLUSION: 1H-MRS enables reliable noninvasive assessment of LFC in patients receiving long-term HPN, if correcting for possible accumulation of paramagnetic components in the liver. However, LFC determination by 1H-MRS is not recommended after a recent ferric compound infusion.

In Alzheimer's disease (AD), defects in essential metabolic processes for energy supply and phospholipid membrane function have been implicated in the pathological process. However, post-mortem investigations are generally limited to late stage disease and prone to tissue decay artifacts. In vivo assessments of high energy phosphates, tissue pH and phospholipid metabolites are possible by phosphorus MR spectroscopy (31P–MRS), but so far only small studies, mostly focusing on single brain regions, have been performed. Therefore, we assessed phospholipid and energy metabolism in multiple brain regions of 31 early stage AD patients and 31 age- and gender-matched controls using 31P–MRS imaging. An increase of phosphocreatine (PCr) was found in AD patients compared with controls in the retrosplenial cortex, and both hippocampi, but not in the anterior cingulate cortex. While PCr/inorganic phosphate and pH were also increased in AD, no changes were found for phospholipid metabolites. This study showed that PCr levels are specifically increased in regions that show early degeneration in AD. Together with an increased pH, this indicates an altered energy metabolism in mild AD., Highlights • Phosphocreatine and pH are increased in mild Alzheimer's disease. • Phosphocreatine increase occurs in early affected brain regions. • Brain energy metabolism may be altered in mild Alzheimer's disease. • Phospholipid and energy metabolites as well as pH, differ across brain regions.

Objective J-difference editing is often used to select resonances of compounds with coupled spins in 1H-MR spectra. Accurate phase and frequency alignment prior to subtracting J-difference-edited MR spectra is important to avoid artefactual contributions to the edited resonance. Materials and methods In-vivo J-difference-edited MR spectra were aligned by maximizing the normalized scalar product between two spectra (i.e., the correlation over a spectral region). The performance of our correlation method was compared with alignment by spectral registration and by alignment of the highest point in two spectra. The correlation method was tested at different SNR levels and for a broad range of phase and frequency shifts. Results In-vivo application of the proposed correlation method showed reduced subtraction errors and increased fit reliability in difference spectra as compared with conventional peak alignment. The correlation method and the spectral registration method generally performed equally well. However, better alignment using the correlation method was obtained for spectra with a low SNR (down to ~2) and for relatively large frequency shifts. Conclusion Our correlation method for simultaneously phase and frequency alignment is able to correct both small and large phase and frequency drifts and also performs well at low SNR levels.

Contains fulltext : 173889.pdf (Publisher’s version ) (Closed access) High-intensity interval training (HIIT) gains increasing popularity in patients with diabetes. HIIT acutely increases plasma lactate levels. This may be important, since administration of lactate during hypoglycemia suppresses symptoms and counterregulation, whilst preserving cognitive function. We tested the hypothesis that HIIT acutely reduces awareness of hypoglycemia and attenuates hypoglycemia-induced cognitive dysfunction. In a randomized crossover trial, patients with type 1 diabetes and normal awareness of hypoglycemia (NAH), patients with impaired awareness of hypoglycemia (IAH), and healthy participants (n=10 per group) underwent a hyperinsulinemic-hypoglycemic (2.6 mmol/L) clamp, either after a HIIT session or after seated rest. Compared to rest, HIIT reduced symptoms of hypoglycemia in patients with NAH, but not in healthy participants or patients with IAH. HIIT attenuated hypoglycemia-induced cognitive dysfunction, which was mainly driven by changes in the NAH subgroup. HIIT suppressed cortisol and growth hormone responses, but not catecholamine responses to hypoglycemia. The present findings demonstrate that a single HIIT session rapidly reduces awareness of subsequent hypoglycemia in patients with type 1 diabetes and NAH, but not in patients with IAH, and attenuates hypoglycemia-induced cognitive dysfunction. The role of exercise-induced lactate in mediating these effects, potentially serving as an alternative fuel for the brain, should be further explored. 9 p.

Contains fulltext : 167188.pdf (Publisher’s version ) (Open Access) Hypoglycemia is the most frequent complication of insulin therapy in patients with type 1 diabetes. Since the brain is reliant on circulating glucose as its main source of energy, hypoglycemia poses a threat for normal brain function. Paradoxically, although hypoglycemia commonly induces immediate decline in cognitive function, long-lasting changes in brain structure and cognitive function are uncommon in patients with type 1 diabetes. In fact, recurrent hypoglycemia initiates a process of habituation that suppresses hormonal responses to and impairs awareness of subsequent hypoglycemia, which has been attributed to adaptations in the brain. These observations sparked great scientific interest into the brain's handling of glucose during (recurrent) hypoglycemia. Various neuroimaging techniques have been employed to study brain (glucose) metabolism, including PET, fMRI, MRS and ASL. This review discusses what is currently known about cerebral metabolism during hypoglycemia, and how findings obtained by functional and metabolic neuroimaging techniques contributed to this knowledge.

Contains fulltext : 108770.pdf (Publisher’s version ) (Closed access) We report on four families affected by a clinical presentation of complex hereditary spastic paraplegia (HSP) due to recessive mutations in DDHD2, encoding one of the three mammalian intracellular phospholipases A(1) (iPLA(1)). The core phenotype of this HSP syndrome consists of very early-onset (

OBJECTIVE To investigate the effect of acute insulin-induced hypoglycemia on cerebral glucose metabolism in healthy humans, measured by 13C magnetic resonance spectroscopy (MRS). RESEARCH DESIGN AND METHODS Hyperinsulinemic glucose clamps were performed at plasma glucose levels of 5 mmol/L (euglycemia) or 3 mmol/L (hypoglycemia) in random order in eight healthy subjects (four women) on two occasions, separated by at least 3 weeks. Enriched [1-13C]glucose 20% w/w was used for the clamps to maintain stable plasma glucose labeling. The levels of the 13C-labeled glucose metabolites glutamate C4 and C3 were measured over time in the occipital cortex during the clamp by continuous 13C MRS in a 3T magnetic resonance scanner. Time courses of glutamate C4 and C3 labeling were fitted using a one-compartment model to calculate metabolic rates in the brain. RESULTS Plasma glucose 13C isotopic enrichment was stable at 35.1 ± 1.8% during euglycemia and at 30.2 ± 5.5% during hypoglycemia. Hypoglycemia stimulated release of counterregulatory hormones (all P < 0.05) and tended to increase plasma lactate levels (P = 0.07). After correction for the ambient 13C enrichment values, label incorporation into glucose metabolites was virtually identical under both glycemic conditions. Calculated tricarboxylic acid cycle rates (VTCA) were 0.48 ± 0.03 μmol/g/min during euglycemia and 0.43 ± 0.08 μmol/g/min during hypoglycemia (P = 0.42). CONCLUSIONS These results indicate that acute moderate hypoglycemia does not affect fluxes through the main pathways of glucose metabolism in the brain of healthy nondiabetic subjects.

ContextPatients with congenital adrenal hyperplasia (CAH) are chronically treated with supraphysiological doses of glucocorticoids, which are known to induce insulin resistance. Thiazolidinediones might reverse this effect and improve insulin sensitivity.ObjectivesTo assess insulin sensitivity in CAH patients and the effect of pioglitazone treatment on insulin sensitivity in CAH patients. Secondary objectives were the effects of treatment with pioglitazone on blood pressure, body fat distribution, lipid, and steroid profiles.DesignRandomized placebo controlled crossover trial.ParticipantsTwelve CAH patients and 12 body mass and age-matched control subjects.InterventionSixteen-week treatment with pioglitazone (45 mg/day) or placebo.Main outcome measureInsulin sensitivity measured by euglycemic clamp and oral glucose tolerance test. Further measures were 24-h blood pressure profiles, body fat distribution measured by magnetic resonance imaging, dual energy x-ray absorptiometry (DEXA) and bioimpedance procedures, liver fat by magnetic resonance spectroscopy, lipid, and steroid profiles.ResultsCAH patients were insulin resistant compared with healthy controls. Treatment with pioglitazone significantly improved insulin sensitivity in CAH patients (glucose infusion rate (GIR) from 28.5±11.6 to 38.9±11.0 μmol/kg per min, P=0.000, GIR in controls 46.2±23.4 μmol/kg per min, PPPConclusionsCAH patients are insulin resistant compared with matched control subjects. Treatment with pioglitazone improves insulin sensitivity and decreases blood pressure in CAH patients.

Contains fulltext : 154736.pdf (Publisher’s version ) (Closed access) Chanarin-Dorfman Syndrome (CDS) is caused by a defect in the CGI-58/ABHD5 gene resulting in a deficiency of CGI-58 and in intracellular accumulation of triacylglycerol in skin and liver. Patients are mainly characterized by congenital ichthyosis, but the clinical phenotype is very heterogeneous. Distinct brain involvement has never been described. We present a clinical description of two patients with congenital ichthyosis. On suspicion of Sjogren-Larsson syndrome (SLS) single-voxel 1H-MR spectroscopy of the brain was performed and biochemical testing of fatty aldehyde dehydrogenase (FALDH) to establish this diagnosis gave normal results. Vacuolisation in a peripheral blood smear has led to the CDS suspicion. In both patients the diagnosis CDS was confirmed by ABHD5 mutation analysis. Interestingly, a clear lipid accumulation in the cerebral white matter, cortex and basal ganglia was demonstrated in both CDS-patients. These results demonstrate, for the first time, cerebral involvement in CDS and give new insights in the complex phenotype. Since the clinical implications of this abnormal cerebral lipid accumulation are still unknown, further studies are warranted.

Contains fulltext : 112411.pdf (Publisher’s version ) (Open Access) A new classification approach was developed to improve the noninvasive diagnosis of brain tumors. Within this approach, information is extracted from magnetic resonance imaging and spectroscopy data, from which the relative location and distribution of selected tumor classes in feature space can be calculated. This relative location and distribution is used to select the best information extraction procedure, to identify overlapping tumor classes, and to calculate probabilities of class membership. These probabilities are very important, since they provide information about the reliability of classification and might provide information about the heterogeneity of the tissue. Classification boundaries were calculated by setting thresholds for each investigated tumor class, which enabled the classification of new objects. Results on histopathologically determined tumors are excellent, demonstrated by spatial maps showing a high probability for the correctly identified tumor class and, moreover, low probabilities for other tumor classes.

Card Sort Test, with the largest correlations observed between binding in the inferior parietal lobule and performance on Block Design (r 1⁄4 0.575, p 1⁄4 0.003). [11 C]PBR28 binding also inversely correlated with gray matter volume in the inferior parietal lobule, superior temporal cortex, middle and inferior temporal cortex, entorhinal cortex, posterior cingulate cortex, and precuneus (p < 0.05). Conclusions: Neuroinflammation, evidenced by increased [11 C]PBR28 binding to TSPO, occurs after conversion of MCI and worsens with AD progression. [11 C]PBR28 may be useful to predict conversion from MCI or to assess treatment response in AD.

Contains fulltext : 127313.pdf (Publisher’s version ) (Open Access) Background Postcancer fatigue is a frequently occurring problem, impairing quality of life. Until now, little is known about (neuro) physiological factors determining postcancer fatigue. For non-cancer patients with chronic fatigue syndrome, certain characteristics of brain morphology and metabolism have been identified in previous studies. We investigated whether these volumetric and metabolic traits are a reflection of fatigue in general and thus also of importance for postcancer fatigue. Methods Fatigued patients were randomly assigned to either the intervention condition (cognitive behavior therapy) or the waiting list condition. Twenty-five patients in the intervention condition and fourteen patients in the waiting list condition were assessed twice, at baseline and six months later. Baseline measurements of 20 fatigued patients were compared with 20 matched non-fatigued controls. All participants had completed treatment of a malignant, solid tumor minimal one year earlier. Global brain volumes, subcortical brain volumes, metabolite tissue concentrations, and metabolite ratios were primary outcome measures. Results Volumetric and metabolic parameters were not significantly different between fatigued and non-fatigued patients. Change scores of volumetric and metabolic parameters from baseline to follow-up were not significantly different between patients in the therapy and the waiting list group. Patients in the therapy group reported a significant larger decrease in fatigue scores than patients in the waiting list group. Conclusions No relation was found between postcancer fatigue and the studied volumetric and metabolic markers. This may suggest that, although postcancer fatigue and chronic fatigue syndrome show strong resemblances as a clinical syndrome, the underlying physiology is different.

Item does not contain fulltext Adenylosuccinate lyase (ADSL) deficiency is a rare inborn error of metabolism resulting in accumulation of metabolites including succinylaminoimidazole carboxamide riboside (SAICAr) and succinyladenosine (S-Ado) in the brain and other tissues. Patients with ADSL have progressive psychomotor retardation, neonatal seizures, global developmental delay, hypotonia, and autistic features, although variable clinical manifestations may make the initial diagnosis challenging. Two cases of the severe form of the disease are reported here: an 18-month-old boy with global developmental delay, intractable neonatal seizures, progressive cerebral atrophy, and marked hypomyelination, and a 3-month-old girl presenting with microcephaly, neonatal seizures, and marked psychomotor retardation. In both patients in vivo proton magnetic resonance spectroscopy (MRS) showed the presence of S-Ado signal at 8.3 ppm, consistent with a prior report. Interestingly, SAICAr signal was also detectable at 7.5 ppm in affected white matter, which has not been reported in vivo before. A novel splice-site mutation, c.IVS12 + 1/G > C, in the ADSL gene was identified in the second patient. Our findings confirm the utility of in vivo proton MRS in suggesting a specific diagnosis of ADSL deficiency, and also demonstrate an additional in vivo resonance (7.5 ppm) of SAICAr in the cases of severe disease. J. Magn. Reson. Imaging 2013;37:974-980. (c) 2012 Wiley Periodicals, Inc.

Contains fulltext : 118937.pdf (Publisher’s version ) (Open Access) Patients with type 1 diabetes mellitus (T1DM) experience, on average, 2 to 3 hypoglycemic episodes per week. This study investigated the effect of hypoglycemia on cerebral glucose metabolism in patients with uncomplicated T1DM. For this purpose, hyperinsulinemic euglycemic and hypoglycemic glucose clamps were performed on separate days, using [1-13C]glucose infusion to increase plasma 13C enrichment. In vivo brain 13C magnetic resonance spectroscopy was used to measure the time course of 13C label incorporation into different metabolites and to calculate the tricarboxylic acid cycle flux (VTCA) by a one-compartment metabolic model. We found that cerebral glucose metabolism, as reflected by the VTCA, was not significantly different comparing euglycemic and hypoglycemic conditions in patients with T1DM. However, the VTCA was inversely related to the HbA1C and was, under hypoglycemic conditions, approximately 45\% higher than that in a previously investigated group of healthy subjects. These data suggest that the brains of patients with T1DM are better able to endure moderate hypoglycemia than those of subjects without diabetes.

A computer aided ultrasound (CAUS) protocol was developed for the diagnosis and staging of hepatic steatosis. Calibration of the fixed imaging preset enables expression of the US parameters relative to the tissue mimicking phantom used and consequently a vendor independent comparison. The CAUS protocol was validated on high yielding dairy cows (n = 151), which severed as a reference model for human non-alcoholic fatty liver disease. The study showed high values for: area under the curve (AROC): 0.94; sensitivity: 87%; specificity: 83%. A pilot study in patients on Home Parenteral Nutrition (HPN, n = 14) and a more extensive study in an obese cohort (n = 116) was performed. Validation was performed by Magnetic Resonance Spectroscopy (MRS). Both studies showed that of all parameters, the residual attenuation coefficient (RAC, the depth dependent mean echo level corrected for beam profile and normal attenuation in liver tissue) has the highest correlation to the reference (MRS fat percentage). For the HPN co...

The objective of this study was to investigate the relationship between plasma and brain glucose levels during euglycemia and hypoglycemia in healthy subjects and patients with type 1 diabetes mellitus (T1DM). Hyperinsulinemic euglycemic (5 mmol/L) and hypoglycemic (3 mmol/L) [1-13C]glucose clamps were performed in eight healthy subjects and nine patients with uncomplicated T1DM (HbA1c 7.7 ± 1.4%). Brain glucose levels were measured by 13C magnetic resonance spectroscopy. Linear regression analysis was used to fit the relationship between plasma and brain glucose levels and calculate reversible Michaelis-Menten (MM) kinetic parameters. Brain glucose values during euglycemia (1.1 ± 0.4 μmol/g vs. 1.1 ± 0.3 μmol/g; P = 0.95) and hypoglycemia (0.5 ± 0.2 μmol/g vs. 0.6 ± 0.3 μmol/g; P = 0.52) were comparable between healthy subjects and T1DM patients. MM kinetic parameters of combined data were calculated to be maximum transport rate/cerebral metabolic rate of glucose (Tmax/CMRglc) = 2.25 ± 0.32 and substrate concentration at half maximal transport (Kt) = 1.53 ± 0.88 mmol/L, which is in line with previously published data obtained under hyperglycemic conditions. In conclusion, the linear MM relationship between plasma and brain glucose can be extended to low plasma glucose levels. We found no evidence that the plasma to brain glucose relationship or the kinetics describing glucose transport over the blood–brain barrier differ between healthy subjects and patients with uncomplicated, reasonably well-controlled T1DM.

Contains fulltext : 97426.pdf (Publisher’s version ) (Closed access) In obesity, insulin-stimulated glucose uptake in skeletal muscle is decreased. We investigated whether the stimulatory effect of acute exercise on glucose uptake and subsequent glycogen synthesis was normal. The study was performed on 18 healthy volunteers, 9 obese (BMI = 32.6 +/- 1.2 kg/m(2), mean +/- SEM) and 9 lean (BMI = 22.0 +/- 0.9 kg/m(2)), matched for age and gender. All participants underwent a euglycemic hyperinsulinemic clamp, showing reduced glucose uptake in the obese group (P = 0.01), during which they performed a short intense local exercise (single-legged toe lifting). Dynamic glucose incorporation into glycogen in the gastrocnemius muscle before and after exercise was assessed by (13)C magnetic resonance spectroscopy combined with infusion of [1-(13)C]glucose. Blood flow was measured to investigate its potential contribution to glucose uptake. Before exercise, glycogen synthesis rate tended to be lower in obese subjects compared with lean (78 +/- 14 vs. 132 +/- 24 mumol/kg muscle/min; P = 0.07). Exercise induced highly significant rises in glycogen synthesis rates in both groups, but the increase in obese subjects was reduced compared with lean (112 +/- 15 vs. 186 +/- 27 mumol/kg muscle/min; P = 0.03), although the relative increase was similar (184 +/- 35 vs. 202 +/- 51%; P = 0.78). After exercise, blood flow increased equally in both groups, without a temporal relationship with the rate of glycogen synthesis. In conclusion, this study shows a stimulatory effect of a short bout of acute exercise on insulin-induced glycogen synthesis rate that is reduced in absolute values but similar in percentages in obese subjects. These results suggest a shared pathway between insulin- and exercise-induced glucose uptake and subsequent glycogen synthesis.

Contains fulltext : 89924_pub.pdf (Publisher’s version ) (Closed access) Contains fulltext : 89924_aut.pdf (author's version ) (Open Access) The effect of insulin-induced hypoglycemia on cerebral glucose metabolism is largely unknown. (13)C MRS is a unique tool to study cerebral glucose metabolism, but the concurrent requirement for [1-(13)C]glucose administration limits its use under hypoglycemic conditions. To facilitate (13)C MRS data analysis we designed separate [1-(13)C]glucose infusion protocols for hyperinsulinemic euglycemic and hypoglycemic clamps in such a way that plasma isotopic enrichment of glucose was stable and comparable under both glycemic conditions. (13)C MR spectra were acquired with optimized (13)C MRS measurement techniques to obtain high quality (13)C MR spectra with these protocols.

Item does not contain fulltext The clinical use of in vivo magnetic resonance spectroscopy (MRS) has been limited for a long time, mainly due to its low sensitivity. However, with the advent of clinical MR systems with higher magnetic field strengths such as 3 Tesla, the development of better coils, and the design of optimized radio-frequency pulses, sensitivity has been considerably improved. Therefore, in vivo MRS has become a technique that is routinely used more and more in the clinic. In this review, the basic methodology of in vivo MRS is described-mainly focused on (1)H MRS of the brain-with attention to hardware requirements, patient safety, acquisition methods, data post-processing, and quantification. Furthermore, examples of clinical applications of in vivo brain MRS in two interesting fields are described. First, together with a description of the major resonances present in brain MR spectra, several examples are presented of deviations from the normal spectral pattern associated with inborn errors of metabolism. Second, through examples of MR spectra of brain tumors, it is shown that MRS can play an important role in oncology. 01 maart 2010

Contains fulltext : 50008.pdf (Publisher’s version ) (Closed access) A computer-based decision support system to assist radiologists in diagnosing and grading brain tumours has been developed by the multi-centre INTERPRET project. Spectra from a database of 1H single-voxel spectra of different types of brain tumours, acquired in vivo from 334 patients at four different centres, are clustered according to their pathology, using automated pattern recognition techniques and the results are presented as a two-dimensional scatterplot using an intuitive graphical user interface (GUI). Formal quality control procedures were performed to standardize the performance of the instruments and check each spectrum, and teams of expert neuroradiologists, neurosurgeons, neurologists and neuropathologists clinically validated each case. The prototype decision support system (DSS) successfully classified 89% of the cases in an independent test set of 91 cases of the most frequent tumour types (meningiomas, low-grade gliomas and high-grade malignant tumours--glioblastomas and metastases). It also helps to resolve diagnostic difficulty in borderline cases. When the prototype was tested by radiologists and other clinicians it was favourably received. Results of the preliminary clinical analysis of the added value of using the DSS for brain tumour diagnosis with MRS showed a small but significant improvement over MRI used alone. In the comparison of individual pathologies, PNETs were significantly better diagnosed with the DSS than with MRI alone.

Contains fulltext : 112351.pdf (Publisher’s version ) (Closed access) PURPOSE: To explore the possibilities of combining multispectral magnetic resonance (MR) images of different patients within one data matrix. MATERIALS AND METHODS: Principal component and linear discriminant analysis was applied to multispectral MR images of 12 patients with different brain tumors. Each multispectral image consisted of T1-weighted, T2-weighted, proton-density-weighted, and gadolinium-enhanced T1-weighted MR images, and a calculated relative regional cerebral blood volume map. RESULTS: Similar multispectral image regions were clustered, while dissimilar multispectral image regions were scattered in a single plot. Both principal component and linear discriminant analysis allowed discrimination between healthy and tumor regions on the image. In addition, linear discriminant analysis allowed discrimination between oligodendrogliomas and astrocytomas. However, the discriminant analysis method was partially capable of recognizing the tumor identity in unknown multispectral images. CONCLUSION: The proposed method may help the radiologist in comparing multispectral MR images of different patients in a more easy and objective way.

Correction to: European Journal of Human Genetics advance online publication, 12 December 2012; doi: 10.1038/ejhg.2012.256 Since the publication of this article the authors have noticed that Judith Fischer’s affiliation was incorrect. The HTML and PDF have been rectified and now carry the correct affiliation.

Contains fulltext : 23768___.PDF (Publisher’s version ) (Open Access)

Since glucose is the main source of energy for the brain, understanding the kinetics of brain glucose uptake under hypoglycemic conditions is highly important. Under normo- and hyperglycemic conditions the relationship between plasma and brain glucose levels is linear and behaves according to reversible Michaelis-Menten (MM) kinetics. In the present study brain glucose levels during hypoglycemia were measured by 13C magnetic resonance spectroscopy (MRS).