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Increased glucose and choline uptake are hallmarks of cancer. We investigated if the uptake and conversion of [2H9]choline alone and together with that of [6,6’ 2H2]glucose can be assessed in subcutaneous tumors by deuterium metabolic imaging (DMI) after bolus administration of these compounds. Therefore tumors with human renal carcinoma cells were grown subcutaneously in mice up to ~0.5 cm3. Mice were anesthetized with isoflurane and IV infused in the MR magnet for ~20 sec with ~0.2 ml solutions containing either [2H9]choline (0.05g/kg) alone or together with [6,6’ 2H2]glucose (1.3g/kg). 2H MR was performed on a 11.7T MR system with a home-built 2H/1H coil using a 900 excitation pulse and 400ms repetition time. 3D DMI was recorded at high resolution (2x2x2mm) in 37 min or at low resolution (3.7x3.7x3.7mm) in 2:24 min. Absolute tissue concentrations were calculate assuming initial [HOD]=13.7mM. Within 5 minutes after [2H9]choline infusion its signal appeared in tumor spectra representing concentration increasing up to 0.3–1.2 mM and then slowly decreased or remained constant over 100 minutes. In plasma [2H9]choline disappeared within 15 minutes post-infusion implying that its tumor signal arises from tissue and not blood. After infusing a mixture of [2H9]choline and [6,6’ 2H2]glucose their signals were observed separately in tumor 2H spectra. Over time the [2H9]choline signal broadened, possibly due to conversion to other choline compounds, [[6,6’ 2H2]glucose] declined, [HOD] increased and a lactate signal appeared, reflecting glycolysis. Metabolic maps of all 2H compounds were reconstructed from high resolution DMIs. As choline infusion and glucose DMI is feasible in patients, their simultaneous detection has clinical potential for tumor characterization.

Good B0 field homogeneity is considered an essential requirement to obtain high-quality MRS data. Many commonly used spectral fitting methods assume that all metabolite signals have Lorentzian or Gaussian shapes. However, B0 inhomogeneity can both broaden the linewidth and modify the lineshape. In this study, it is hypothesized that a realistic metabolite fitting model, which accounts for B0 homogeneity on the basis of the water lineshape, will improve the accuracy of estimation of metabolite concentrations. In-vivo water suppressed/unsuppressed single voxel spectroscopy signals were acquired under three different B0 field homogeneity regimes. Individual realistic basis sets were created for each acquisition. Frequency-domain spectral fitting with LCModel was used to quantify the metabolite concentrations with fitting uncertainties given in terms of the Cramer-Rao lower bound. The quantification results obtained using the water lineshape basis set yielded similar concentrations independent of linewidth and showed a larger fitting error as the linewidth increased. The conventional approach, however quantifies metabolite concentrations with greater variations despite showing a supposedly improved fitting quality. The water lineshape basis set achieved single voxel spectroscopy accuracy that is less sensitive to the linewidth compared to the conventional spectral fitting method for the range of linewidths used in this study, but the precision deteriorated with worsening B0 field inhomogeneity. The beneficial effect was ascribed to a reduction in the number of degrees of freedom when using the water lineshape to generate the basis set.

Disruptive behavior is associated with societally and personally problematic levels of aggression and has been linked to abnormal structure and function of fronto-amygdalastriatal regions. Abnormal glutamatergic signalling within this network may play a role in aggression. However, disruptive behavior does not represent a homogeneous construct, but can be fractionated across several dimensions. Of particular interest, callous-unemotional (CU) traits have been shown to modulate the severity, neural and behavioural characterisation, and therapeutic outcomes of disruptive behaviour disorders (DBDs) and aggression. Further, individuals showing disruptive behavior differ to the extent that they engage in subtypes of aggression (i.e., proactive [PA] and reactive aggression [RA]) which may also represent distinct therapeutic targets. Here we investigated how glutamate signalling within the fronto-amygdala-striatal circuitry was altered along these dimensions in youths showing disruptive behavior (n = 140) and typically developing controls (TD, n = 93) within the age-range of 8-18 years. We used proton magnetic resonance spectroscopy (H-1-MRS) in the anterior cingulate cortex (ACC), striatum, amygdala and insula and associated glutamate concentrations with continuous measures of aggression and CU-traits using linear mixed-effects models. We found evidence of a dissociation for the different measures and glutamate concentrations. CU traits were associated with increased ACC glutamate ('callousness': b=.19, t (108) = 2.63, p=.01, r=.25; 'uncaring': b=.18, t (108) = 2.59, p=.011, r=.24) while PA was associated with decreased striatal glutamate concentration (b = -.23, t (28) = -3.02, p=.005, r=.50). These findings suggest dissociable correlates of CU traits and PA in DBDs, and indicate that the ACC and striatal glutamate may represent novel pharmacological targets in treating these different aspects. (C) 2019 Elsevier Ltd. All rights reserved.

Simple Summary Tumors increase their glucose and choline uptake to support growth. These properties are employed to detect and identify tumors in the body by imaging the uptake of radio-isotope analogs of these compounds. In this study we show that deuterium metabolic imaging (DMI) (a new MRI method to image metabolites using non-radioactive labeling with deuterium) can image choline uptake in tumors. Furthermore, we demonstrate that DMI can image the tumor uptake of choline and glucose (and additionally its metabolic conversion) simultaneously, in contrast to radio-isotope imaging, which only assesses the uptake of one radio-isotope labeled compound at a time. For these reasons (and also because DMI is relatively simple and can be combined with other MR methods), it is a promising modality for a more specific tumor characterization than by separate imaging of the uptake of radio-isotope labeled glucose or choline. Abstract Increased glucose and choline uptake are hallmarks of cancer. We investigated whether the uptake and conversion of [2H9]choline alone and together with that of [6,6′-2H2]glucose can be assessed in tumors via deuterium metabolic imaging (DMI) after administering these compounds. Therefore, tumors with human renal carcinoma cells were grown subcutaneously in mice. Isoflurane anesthetized mice were IV infused in the MR magnet for ~20 s with ~0.2 mL solutions containing either [2H9]choline (0.05 g/kg) alone or together with [6,6′-2H2]glucose (1.3 g/kg). 2H MR was performed on a 11.7T MR system with a home-built 2H/1H coil using a 90° excitation pulse and 400 ms repetition time. 3D DMI was recorded at high resolution (2 × 2 × 2 mm) in 37 min or at low resolution (3.7 × 3.7 × 3.7 mm) in 2:24 min. Absolute tissue concentrations were calculated assuming natural deuterated water [HOD] = 13.7 mM. Within 5 min after [2H9]choline infusion, its signal appeared in tumor spectra representing a concentration increase to 0.3–1.2 mM, which then slowly decreased or remained constant over 100 min. In plasma, [2H9]choline disappeared within 15 min post-infusion, implying that its signal arises from tumor tissue and not from blood. After infusing a mixture of [2H9]choline and [6,6′-2H2]glucose, their signals were observed separately in tumor 2H spectra. Over time, the [2H9]choline signal broadened, possibly due to conversion to other choline compounds, [[6,6′-2H2]glucose] declined, [HOD] increased and a lactate signal appeared, reflecting glycolysis. Metabolic maps of 2H compounds, reconstructed from high resolution DMIs, showed their spatial tumor accumulation. As choline infusion and glucose DMI is feasible in patients, their simultaneous detection has clinical potential for tumor characterization.

Magnetic susceptibility differences between grey matter (GM) and white matter (WM) can potentially affect lineshapes and chemical shifts in single-voxel spectroscopy. This study aimed to investigate the consequences and potential utility of these effects. Spectroscopy voxels were segmented into GM, WM, and cerebrospinal fluid based on T1-weighted images. GM and WM lineshapes were computed using multi-echo gradient-echo images to measure the frequency distribution. Twenty 7 Tesla single voxel spectra with corresponding T1-weighted images were acquired from the frontal and parietal lobes from five healthy human volunteers. Consistent frequency shifts (mean [±SD] 4.9 ± 2.0 Hz) and linewidth differences (2.4 ± 1.5 Hz) between the two tissue types were observed. Directly visible metabolites (creatine, choline, and myo-inositol) exhibited frequency shifts and linewidth differences that were consistent with a linear-weighted summation of their expected GM and WM distribution ratios. The magnetic susceptibility difference between GM and WM had a detectable effect on single-voxel proton spectra, which results in both frequency shifts and lineshape broadening. This effect can be used to estimate the relative metabolic distribution in the GM and WM for directly observable metabolites. Fractional distributions estimated with this method demonstrated good agreement with literature values for the selected metabolites.

Obsessive–compulsive disorder (OCD) is a neuropsychiatric disorder with childhood onset, and is characterized by intrusive thoughts and fears (obsessions) that lead to repetitive behaviors (compulsions). Previously, we identified insulin signaling being associated with OCD and here, we aim to further investigate this link in vivo. We studied TALLYHO/JngJ (TH) mice, a model of type 2 diabetes mellitus, to (1) assess compulsive and anxious behaviors, (2) determine neuro-metabolite levels by 1 H magnetic resonance spectroscopy (MRS) and brain structural connectivity by diffusion tensor imaging (DTI), and (3) investigate plasma and brain protein levels for molecules previously associated with OCD (insulin, Igf1, Kcnq1, and Bdnf) in these subjects. TH mice showed increased compulsivity-like behavior (reduced spontaneous alternation in the Y-maze) and more anxiety (less time spent in the open arms of the elevated plus maze). In parallel, their brains differed in the white matter microstructure measures fractional anisotropy (FA) and mean diffusivity (MD) in the midline corpus callosum (increased FA and decreased MD), in myelinated fibers of the dorsomedial striatum (decreased FA and MD), and superior cerebellar peduncles (decreased FA and MD). MRS revealed increased glucose levels in the dorsomedial striatum and increased glutathione levels in the anterior cingulate cortex in the TH mice relative to their controls. Igf1 expression was reduced in the cerebellum of TH mice but increased in the plasma. In conclusion, our data indicates a role of (abnormal) insulin signaling in compulsivity-like behavior.

Contains fulltext : 216029.pdf (Publisher’s version ) (Open Access) Parkinson's disease is characterized by bradykinesia, rigidity, and tremor. These symptoms have been related to an increased gamma‐aminobutyric acid (GABA)ergic inhibitory drive from globus pallidus onto the thalamus. However, in vivo empirical evidence for the role of GABA in Parkinson's disease is limited. Some discrepancies in the literature may be explained by the presence or absence of tremor. Specifically, recent functional magnetic resonance imaging (fMRI) findings suggest that Parkinson's tremor is associated with reduced, dopamine‐dependent thalamic inhibition. Here, we tested the hypothesis that GABA in the thalamocortical motor circuit is increased in Parkinson's disease, and we explored differences between clinical phenotypes. We included 60 Parkinson patients with dopamine‐resistant tremor (n = 17), dopamine‐responsive tremor (n = 23), or no tremor (n = 20), and healthy controls (n = 22). Using magnetic resonance spectroscopy, we measured GABA‐to‐total‐creatine ratio in motor cortex, thalamus, and a control region (visual cortex) on two separate days (ON and OFF dopaminergic medication). GABA levels were unaltered by Parkinson's disease, clinical phenotype, or medication. However, motor cortex GABA levels were inversely correlated with disease severity, particularly rigidity and tremor, both ON and OFF medication. We conclude that cortical GABA plays a beneficial rather than a detrimental role in Parkinson's disease, and that GABA depletion may contribute to increased motor symptom expression. 13 p.

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

PURPOSE: A relatively high signal for choline-containing compounds (total choline, tCho) is commonly found in (1) H MR spectra of malignant tumors, but it is unclear if this also occurs in tumors in the liver. We evaluated the potential of the tCho signal in single voxel (1) H MR spectra of the human liver to assess metastases of colorectal cancers. EXPERIMENT: MR spectra of an 8 cm(3) PRESS-localized voxel were obtained at 3 T from the livers of 12 healthy volunteers and from metastatic lesions in 20 patients in two different sessions. To correct for motion artifacts, sequentially recorded spectra were individually phased and frequency aligned before averaging. Spectra were analyzed using LCModel and tissue levels estimated by water referencing. Repeatability was assessed with Bland-Altman analyses. To estimate tumor necrosis, diffusion-weighted imaging of the liver was performed. High resolution magic angle spinning (HRMAS) spectra of tumor and normal liver samples were obtained at 11.7 T. RESULTS: With increasing tumor volumes, tCho levels decreased, indicating a partial volume effect. Mean tCho content in tumors larger than the PRESS voxel (>8 cm(3) ) was significantly lower (p < 0.01) than for normal liver: 1.6 (range 0.0-3.4) versus 6.9 (range 4.9-11.1) mmol/kg wet weight, while it was comparable for tumors smaller than 8 cm(3) : 7.0 (range 3.8-9.3) mmol/kg. The higher 90th percentile apparent diffusion coefficient value in the larger lesions indicates more necrosis. Measurement repeatability was average in normal livers and poor in tumors. HRMAS did not show substantial differences in choline-containing compounds between normal liver and metastasis. CONCLUSION: An increased tCho content was not observed in (1) H MR spectra of liver metastasis of colorectal cancer, compared with normal liver. This may be due to the background of a high tCho signal in spectra of normal liver or to an intrinsic lower tCho content in these tumors, but is most likely the result of necrosis in metastatic tumor tissue.

γ-Aminobutyric acid (GABA), the major inhibitory neurotransmitter, is challenging to measure using proton spectroscopy due to its relatively low concentration, J-coupling and overlapping signals from other metabolites. Currently, the prevalent methods for detecting GABA at ultrahigh field strengths (≥ 7 T) are GABA-editing and model fitting of non-editing single voxel spectra. These two acquisition approaches have their own advantages: the GABA editing approach directly measures the GABA resonance at 3 ppm, whereas the fitting approach on the non-editing spectrum allows the detection of multiple metabolites, and has an SNR advantage over longer echo time (TE) acquisitions. This study aims to compare these approaches for estimating GABA at 7 T. We use an interleaved sequence of semi- LASER (sLASER: TE = 38 ms) and MEGA-sLASER (TE = 80 ms). This simultaneous interleaved acquisition minimizes the differential effect of extraneous factors, and enables an accurate comparison of the two acquisition methods. Spectra were acquired with an 8 ml isotropic voxel at six different brain regions: anterior-cingulate cortex, dorsolateral-prefrontal cortex, motor cortex, occipital cortex, posterior cingulate cortex, and precuneus. Spectral fitting with LCModel quantified the GABA to total Cr (tCr: Creatine + Phosphocreatine) concentration ratio. After correcting the T₂ relaxation time variation, GABA/tCr ratios were similar between the two acquisition approaches. GABA editing showed smaller spectral fitting error according to Cramér-Rao lower bound than the sLASER approach for all regions examined. We conclude that both acquisition methods show similar accuracy but the precision of the MEGA-editing approach is higher for GABA measurement. In addition, the 2.28 ppm GABA resonance was found to be important for estimating GABA concentration without macromolecule contamination in the GABA-edited acquisition, when utilizing spectral fitting with LCModel. CA - Donghyun

Volume selection in (1) H MR spectroscopic imaging (MRSI) of the prostate is commonly performed with low-bandwidth refocusing pulses. However, their large chemical shift displacement error (CSDE) causes lipid signal contamination in the spectral range of interest. Application of high-bandwidth adiabatic pulses is limited by radiofrequency (RF) power deposition. In this study, we aimed to provide an MRSI sequence that overcomes these limitations.Measurements were performed at 3 T with an endorectal receive coil. A semi-LASER sequence was equipped with low RF power demanding gradient-modulated offset-independent adiabaticity (GOIA) refocusing pulses with WURST(16,4) modulation, with a 10 kHz bandwidth.Simulations and phantom studies verified that the GOIA pulses select slices with a flat top and sharp edges and minimal CSDE. The sequence timing was tuned to an optimal citrate signal shape at an echo time of 88 ms. Patient studies (nn=n10) demonstrated that high quality spectra with reduced lipid artifacts can be obtained from the whole prostate. Compared with PRESS acquisition at 145 ms the signal-to-noise ratio (SNR) of citrate is increased up to 2.6 and choline up to 1.3.An MRSI sequence of the prostate is presented with minimized spectral lipid contamination and improved SNR, to facilitate routine clinical acquisition of metabolic data. Magn Reson Med, 2014. © 2014 Wiley Periodicals, Inc.

PURPOSE: A semi-LASER sequence was optimized for in vivo lactate detection in the prostate. METHODS: The ethical committee waived the need for informed consent to measure 17 patients with high grade prostate cancer on a 3T system. A semi-LASER sequence was used with an echo time of 144 ms and optimized interpulse timing for a spectral citrate shape with high signal intensity. An LCModel basis set was developed for fitting choline, creatine, spermine, citrate, and lactate and was used to fit all spectra in tumor-containing voxels. For patients without detectable lactate, the minimal detectable lactate concentration was determined by adding in all spectra of tumor tissue a simulated lactate signal. The amplitude of the simulated lactate signal was iteratively decreased until its fit reached a Cramer Rao lower bound >20\%, which was then set as the patient-specific detection limit. RESULTS: In none of the patients a convincing lactate signal was found. We estimated that on average the lactate levels in high grade prostate cancer are below 1.5 mM (range 0.9-3.5 mM), Interestingly, in one patient with extensive necrosis in the tumor biopsy samples (Gleason score 5+5), large lipid resonances were observed, which originated from the tumor. CONCLUSION: The minimal detectable lactate concentration of 1.5 mM in high grade prostate cancer indicates that if lactate is increased it remains at low concentrations. Magn Reson Med, 2013. © 2013 Wiley Periodicals, Inc.

Purpose: To assess the reproducibility of 1H-MR spectroscopic imaging (MRSI) of the human brain at 3T with volume selection by a double spin echo sequence for localization with adiabatic refocusing pulses (semi-LASER). Materials and Methods: Twenty volunteers in two different institutions were measured twice with the same pulse sequence at an echo time of 30 msec. Magnetic resonance (MR) spectra were analyzed with LCModel with a simulated basis set including an experimentally acquired macromolecular signal profile. For specific regions in the brain mean metabolite levels, within and between subject variance, and the coefficient of variation (CoV) were calculated (for taurine, glutamate, total N-acetylaspartate, total creatine, total choline, myo-inositol + glycine, and glutamate + glutamine). Results: Repeated measurements showed no significant differences with a paired t-test and a high reproducibility (CoV ranging from 3%–30% throughout the selected volume). Mean metabolite levels and CoV obtained in similar regions in the brain did not differ significantly between two contributing institutions. The major source of differences between different measurements was identified to be the between-subject variations in the volunteers. Conclusion: We conclude that semi-LASER 1H-MRSI at 3T is an adequate method to obtain quantitative and reproducible measures of metabolite levels over large parts of the brain, applicable across multiple centers. J. Magn. Reson. Imaging 2010;31:61–70. © 2009 Wiley-Liss, Inc.

Contains fulltext : 80003.pdf (Publisher’s version ) (Closed access) Contains fulltext : 80003-1.pdf (Author’s version postprint ) (Open Access) In this study, we examined the in vivo relationship between functional tumor vasculature, determined by dynamic contrast-enhanced (DCE-) MRI, and tumor metabolism, determined by dynamic (18)F-FDG PET, during cytotoxic treatment of patients with colorectal liver metastases. METHODS: Twenty-three patients underwent DCE-MRI (using gadolinium dimeglumine) and dynamic (18)F-FDG PET at baseline and after 3 treatment cycles, unless treatment was terminated because of toxicity. Parameters for vasculature (rate constant between extravascular extracellular space and blood plasma [k(ep)] and volume transfer constant [K(trans)]), extracellular space (v(e)), tumor size (the maximal axial diameter of each included lesion [MAD]), and metabolism (glucose metabolic rates [MR(glc)]) were derived, and changes during treatment were correlated. Overall survival (OS) and progression-free survival (PFS) served as outcome measures for the predictive abilities of pretreatment parameters and of treatment-related parameter changes. RESULTS: Pretreatment MR(glc) and MAD were individually predictive for OS and PFS. During treatment, K(trans) increased significantly, but this increase could not be confirmed in a lesion-by-lesion analysis. MR(glc) decreased significantly (P < 0.001). No correlations were found for changes in DCE-MRI parameters and DeltaMR(glc). No relationship was found between changes in DCE-MRI parameters and OS or PFS. DeltaMR(glc) was able to predict OS (P = 0.008) after correction for confounders. CONCLUSION: The efficacy of cytotoxic chemotherapy assessed by reduction in tumor metabolism does not depend on pretreatment properties of the tumor vasculature determined by DCE-MRI. Cytotoxic chemotherapy does not alter DCE-MRI-derived properties of tumor vasculature but decreases glucose consumption of tumor cells.

Background Docetaxel is one of the most frequently used drugs to treat breast cancer. However, resistance or incomplete response to docetaxel is a major challenge. The aim of this study was to utilize MR metabolomics to identify potential biomarkers of docetaxel resistance in a mouse model for BRCA1-mutated breast cancer. Methodology High resolution magic angle spinning (HRMAS) 1H MR spectroscopy was performed on tissue samples obtained from docetaxel-sensitive or -resistant BRCA1-mutated mammary tumors in mice. Measurements were performed on samples obtained before treatment and at 1-2, 3-5 and 6-7 days after a 25 mg/kg dose of docetaxel. The MR spectra were analyzed by multivariate analysis, followed by analysis of the signals of individual compounds by peak fitting and integration with normalization to the integral of the creatine signal and of all signals between 2.9 and 3.6 ppm. Results The HRMAS spectra revealed significant metabolic differences between sensitive and resistant tissue samples. In particular choline metabolites were higher in resistant tumors by more than 50% with respect to creatine and by more than 30% with respect to all signals between 2.9 and 3.6 ppm. Shortly after treatment (1-2 days) the normalized choline metabolite levels were significantly increased by more than 30% in the sensitive group coinciding with the time of highest apoptotic activity induced by docetaxel. Thereafter, choline metabolites in these tumors returned towards pre-treatment levels. No change in choline compounds was observed in the resistant tumors over the whole time of investigation. Conclusions Relative tissue concentrations of choline compounds are higher in docetaxel resistant than in sensitive BRCA1-mutated mouse mammary tumors, but in the first days after docetaxel treatment only in the sensitive tumors an increase of these compounds is observed. Thus both pre- and post-treatment tissue levels of choline compounds have potential to predict response to docetaxel treatment. © 2015 van Asten et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public DomainDedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,unless otherwise stated.

Contains fulltext : 57305.pdf (Publisher’s version ) (Closed access) Localized in vivo 1H magnetic resonance spectroscopy (MRS) was used to investigate metabolite levels in the brain of adult Zucker Diabetic Fatty (ZDF) rats, an animal model for type 2 diabetes mellitus. This study focussed on the hippocampus, assumed to be one of the main brain areas affected by this disease. Together with an almost 5-fold increase in blood glucose concentration measured by glucose oxidation, significant increases were found in the hippocampal concentrations of glucose (4.93 vs 1.66 mM p < 0.001), myo-inositol (6.52 vs 4.30 mM; p < 0.05), and total creatine (12.71 vs 10.50 mM; p < 0.05) in ZDF rats (n = 5) compared with littermates (n = 5). Although no obvious alterations were detected in the hippocampal levels of other metabolites, including NAA + NAAG and choline-containing compounds in the ZDF rats, the increase in Glc and Ins levels is in line with elevated brain tissue contents of these metabolites in patients with diabetes mellitus.

Item does not contain fulltext As a model for guanidinoacetate methyltransferase (GAMT) deficiency in humans, a gene knockout mouse model was generated. Here we report on several metabolic abnormalities in these mice, observed by in vivo and in vitro MR spectroscopy. In (1)H MR spectra of brain and hindleg muscle a clearly reduced signal of creatine (Cr) was observed in GAMT-deficient (GAMT-/-) animals. Analysis of the (1)H MR spectra of GAMT-/- brain indicated little or no increase of a signal for guanidinoacetate (Gua). In proton MR spectra of muscle, a broad signal of low intensity was observed for Gua. However, substantial Gua accumulation in intact muscle tissue was unequivocally confirmed in high-resolution magic angle spinning spectra, in which the Gua signal was resolved as one clear sharp singlet. In (31)P MR analysis of brain and hindleg muscle a strongly reduced phosphocreatine (PCr) content was shown. In addition, a signal of phosphorylated Gua at 0.5 ppm upfield of PCr was observed, with much higher intensity in muscle than in brain. This signal decreased when ischemia was applied to the muscle and recovered after ischemia was released. Overall, the in vivo (31)P and (1)H MR spectroscopy of GAMT-/- mice is similar to that of human GAMT deficiency. This opens up new avenues for the fundamental study of tissue-type dependence of creatine synthesis and transport and for diagnostic and therapeutic aspects of creatine deficiencies in humans.

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 In patients with Alzheimer's disease (AD) the severity of white matter degeneration correlates with the clinical symptoms of the disease. In this study, we performed diffusion-tensor magnetic resonance imaging at ultra-high field in a mouse model for AD (APP(swe)/PS1(dE9)) in combination with a voxel-based approach and tractography to detect changes in water diffusivity in white and gray matter, because these reflect structural alterations in neural tissue. We found substantial changes in water diffusion parallel and perpendicular to axonal tracts in several white matter regions like corpus callosum and fimbria of the hippocampus, that match with previous findings of axonal disconnection and myelin degradation in AD patients. Moreover, we found a significant increase in diffusivity in specific hippocampal subregions, which is supported by neuronal loss as visualized with Kluver-Barrera staining. This work demonstrates the potential of ultra-high field diffusion-tensor magnetic resonance imaging as a noninvasive modality to describe white and gray matter structural changes in mouse models for neurodegenerative disorders, and provides valuable knowledge to assess future AD prevention strategies in translational research.

Item does not contain fulltext INTRODUCTION: To understand which factors could affect the assessment of anti-vascular treatment by DCE-MRI, we investigated possible causes that could have hampered the selection of an optimal biological dose in humans of the vascular targeted agent NGR-hTNF by DCE-MRI: (1) insufficient reproducibility of DCE-MRI; (2) less specific targeting of NGR-hTNF; (3) interference of vessel characteristics with NGR-hTNF efficacy; (4) interfering pharmacodynamic effects. EXPERIMENTAL: In a phase I study NGR-hTNF, DCE-MRI was performed at baseline and 2h after NGR-hTNF administration in 31 patients with advanced solid cancer. Reproducibility measurements were performed in 5 other non-treated patients with metastatic disease. Mean k(ep), K(trans) values and their histogram distribution were determined in metastases and healthy liver tissue. The correlation between tumour size and DCE-MRI parameters was determined. Kinetics of soluble TNF receptors and the development of anti-TNF antibodies were assessed. RESULTS: Reproducibility of the DCE-MRI technique was adequate. Mean DCE-MRI parameters did not significantly change after NGR-hTNF administration, but histogram analyses showed significant changes in metastases and healthy liver tissue in some patients. The anti-vascular effects of NGR-hTNF were larger in smaller tumours, which have less mature neovasculature. Soluble TNF receptors were released. CONCLUSIONS: The difficulty to find an optimal biological dose of NGR-TNF by DCE-MRI is likely caused by a combination of factors: (i) different profiles of early anti-vascular effects in tumours and healthy liver tissue, (ii) dependence of the magnitude of the anti-vascular effect of NGR-hTNF on tumour size and (iii) shedding kinetics of soluble TNFalpha receptors.

Purpose: This phase I trial investigating the vascular targeting agent NGR-hTNF aimed to determine the (a) dose-limiting toxicities, (b) maximum tolerated dose (MTD), (c) pharmacokinetics and pharmacodynamics, (d) vascular response by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and (e) preliminary clinical activity in solid tumors. Experimental Design: NGR-hTNF was administered once every 3 weeks by a 20- to 60-minute i.v. infusion to cohorts of three to six patients with solid tumors in escalating doses. Pharmacokinetic and pharmacodynamic analyses in blood were done during the first four cycles. DCE-MRI was done in cycle 1 at baseline and 2 hours after the start of the infusion. Results: Sixty-nine patients received a total of 201 cycles of NGR-hTNF (0.2-60 μg/m2). Rigors and fever were the most frequently observed toxicities. Four dose-limiting toxicities were observed (at doses of 1.3, 8.1, and 60 μg/m2), of which three were infusion related. The MTD was 45 μg/m2. The mean apparent terminal half-life ranged from 0.963 to 2.08 hours. DCE-MRI results of tumors showed a vascular response to NGR-hTNF. No objective responses were observed, but 27 patients showed stable disease with a median duration of 12 weeks. Conclusions: NGR-hTNF was well tolerated. The MTD was 45 μg/m2 administered in 1 hour once every 3 weeks. DCE-MRI results showed the antivascular effect of NGR-hTNF. These findings call for further research for defining the optimal biological dose and clinical activity of NGR-hTNF as a single agent or in combination with cytotoxic drugs. Clin Cancer Res; 16(4); 1315–23

Histopathology of prostate needle biopsies (PNBs) is an important part in the diagnosis, prognosis and treatment evaluation of prostate cancer. The determination of metabolite levels in the same biopsies may have additional clinical value. Here, we demonstrate the use of non-destructive high resolution magic angle spinning (HRMAS) proton NMR Spectroscopy for the assessment of metabolic profiles of prostate tissue in PNBs as commonly obtained in standard clinical practice.PNBs that were taken routinely from 48 patients suspected of having prostate cancer were subjected to HRMAS proton NMR spectroscopy. Subsequent histopathology of the same biopsies classified the tissue either as cancer (n = 10) or benign (n = 30).Some practical aspects of this assessment were evaluated, such as typical spectral contamination caused by the PNB procedure. Significant metabolic differences were found between malignant and benign tissue using a small set of ratio's involving signals of choline compounds, citrate and lactate. Moreover, significant correlations were observed between choline, total choline, and citrate over creatine signal ratios and the Gleason scores of tumor in PNBs and of tumor in the whole prostate.This preliminary study indicates that HRMAS NMR of routinely obtained PNBs can provide detailed metabolic information of intact prostate tissue with clinical relevance.

Creatine (Cr) levels in skeletal muscle and brain of a mouse model of Cr deficiency caused by guanidinoacetate methyltransferase absence (GAMT−/−) were studied after Cr supplementation with 2 g·kg body wt−1·day−1Cr for 35 days. Localized1H magnetic resonance spectroscopy (MRS) was performed in brain (cerebellum and thalamus/hippocampus) and in hind leg muscle of GAMT−/−mice before and after Cr supplementation and in control (Con) mice. As expected, a signal for Cr was hardly detectable in MR spectra of GAMT−/−mice before Cr supplementation. In the thalamus/hippocampus region of these mice, an increase in N-acetylasparate (NAA) was observed. During Cr administration, Cr levels increased faster in skeletal muscle compared with brain, but this occurred only during the first day of supplementation. Thereafter, Cr levels increased by 0.8 mM/day in all studied locations. After 35 days of Cr supplementation, Cr levels in all locations were higher compared with Con mice on a Cr-free diet and NAA levels normalized. Only because of the repeated MRS measurements performed in this longitudinal Cr supplementation study on GAMT−/−mice were we able to discover the initial faster uptake of Cr in skeletal muscle compared with brain, which may represent muscular Cr uptake independent of Cr transporter expression. Our results can provide the basis for additional experiments to optimize Cr supplementation in GAMT deficiency, as increases in brain Cr are slow in patients after Cr supplementation.

Contains fulltext : 32331.pdf (Publisher’s version ) (Closed access) The purpose of this paper is to evaluate the effect of the combination of magnetic resonance spectroscopic imaging (MRSI) data and magnetic resonance imaging (MRI) data on the classification result of four brain tumor classes. Suppressed and unsuppressed short echo time MRSI and MRI were performed on 24 patients with a brain tumor and four volunteers. Four different feature reduction procedures were applied to the MRSI data: simple quantitation, principal component analysis, independent component analysis and LCModel. Water intensities were calculated from the unsuppressed MRSI data. Features were extracted from the MR images which were acquired with four different contrasts to comply with the spatial resolution of the MRSI. Evaluation was performed by investigating different combinations of the MRSI features, the MRI features and the water intensities. For each data set, the isolation in feature space of the tumor classes, healthy brain tissue and cerebrospinal fluid was calculated and visualized. A test set was used to calculate classification results for each data set. Finally, the effect of the selected feature reduction procedures on the MRSI data was investigated to ascertain whether it was more important than the addition of MRI information. Conclusions are that the combination of features from MRSI data and MRI data improves the classification result considerably when compared with features obtained from MRSI data alone. This effect is larger than the effect of specific feature reduction procedures on the MRSI data. The addition of water intensities to the data set also increases the classification result, although not significantly. We show that the combination of data from different MR investigations can be very important for brain tumor classification, particularly if a large number of tumors are to be classified simultaneously. Copyright (C) 2005 John Wiley Sons, Ltd.

e13525 Background: Vascular targeted TNF (NGR-hTNF) has antivascular properties. In a recent phase I study (EORTC 16041) it was not possible to select an optimal biological dose of NGR-hTNF from DC...

Item does not contain fulltext Fructose consumption has been associated with the surge in obesity and dyslipidemia. This may be mediated by the fructose effects on hepatic lipids and ATP levels. Fructose metabolism provides carbons for de novo lipogenesis (DNL) and stimulates enterocyte secretion of apoB48. Thus, fructose-induced hepatic triglyceride (HTG) accumulation can be attributed to both DNL stimulation and dietary lipid absorption. The aim of this study was to assess the effects of fructose diet on HTG and ATP content and the contributions of dietary lipids and DNL to HTG. Measurements were performed in vivo in mice by magnetic resonance imaging (MRI) and novel magnetic resonance spectroscopy (MRS) approaches. Abdominal adipose tissue volume and intramyocellular lipid levels were comparable between 8-wk fructose- and glucose-fed mice. HTG levels were ∼1.5-fold higher in fructose-fed than in glucose-fed mice (P