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Mutations of the isocitrate dehydrogenase 1 and 2 genes ( IDH1 and IDH2 ) are commonly found in primary brain cancers. We previously reported that a novel enzymatic activity of these mutations results in the production of the putative oncometabolite, R(−)-2-hydroxyglutarate (2-HG). Here we investigated the ability of magnetic resonance spectroscopy (MRS) to detect 2-HG production in order to non-invasively identify patients with IDH1 mutant brain tumors. Patients with intrinsic glial brain tumors ( n  = 27) underwent structural and spectroscopic magnetic resonance imaging prior to surgery. 2-HG levels from MRS data were quantified using LC-Model software, based upon a simulated spectrum obtained from a GAMMA library added to the existing prior knowledge database. The resected tumors were then analyzed for IDH1 mutational status by genomic DNA sequencing, Ki-67 proliferation index by immunohistochemistry, and concentrations of 2-HG and other metabolites by liquid chromatography–mass spectrometry (LC–MS). MRS detected elevated 2-HG levels in gliomas with IDH1 mutations compared to those with wild-type IDH1 ( P  = 0.003). The 2-HG levels measured in vivo with MRS were significantly correlated with those measured ex vivo from the corresponding tumor samples using LC–MS ( r 2  = 0.56; P  = 0.0001). Compared with wild-type tumors, those with IDH1 mutations had elevated choline ( P  = 0.01) and decreased glutathione ( P  = 0.03) on MRS. Among the IDH1 mutated gliomas, quantitative 2-HG values were correlated with the Ki-67 proliferation index of the tumors ( r 2  = 0.59; P  = 0.026). In conclusion, water-suppressed proton ( 1 H) MRS provides a non-invasive measure of 2-HG in gliomas, and may serve as a potential biomarker for patients with IDH1 mutant brain tumors. In addition to 2-HG, alterations in several other metabolites measured by MRS correlate with IDH1 mutation status.

Skeletal muscle's capacity for oxidative energy production can be measured in vivo by phosphocreatine (PCr) recovery following maximal contractions inside a magnetic resonance scanner. However, muscle energetic characteristics during submaximal contractions of similar intensity as used in free‐living activities may be more relevant to the energetic support of ambulatory tasks during daily life. We measured vastus lateralis muscle oxidative capacity, acidification, submaximal oxidative energy production, and acetylcarnitine accumulation in response to an incremental contraction protocol (6%–15% maximal torque). We then evaluated the relationships between these metrics and whole‐body metabolic responses to a 30‐min treadmill walk (30MTW) and a peak oxygen consumption (VO2peak) test using Spearman rank correlations (rs, n = 7 males, 28 ± 4 years). Muscle oxidative capacity was not related to any metric of whole‐body metabolism, but submaximal PCr recovery was associated with slower VO2 off‐kinetics following the 30MTW (rs = 0.96, p = 0.003). Muscle [acetylcarnitine] was associated with respiratory exchange ratio (RER) during the 30MTW and VO2peak test (rs = 0.81, p = 0.035 and rs = 0.86, p = 0.024). Muscle acidification was associated with RER only at VO2peak (and rs = −0.89, p = 0.012). These preliminary results provide novel connections between muscle and whole‐body energetics and suggest that submaximal muscle energetics may be more relevant to free‐living tasks than oxidative capacity. Role of muscle energetics in metabolic response to ambulation.

Background Mutations in the isocitrate dehydrogenase enzyme are present in a majority of lower-grade gliomas and secondary glioblastomas. This mis-sense mutation results in the neomorphic reduction of isocitrate dehydrogenase resulting in an accumulation of the “oncometabolite” 2-hydroxyglutarate (2HG). Detection of 2HG can thus serve as a surrogate biomarker for these mutations, with significant translational implications including improved prognostication. Two dimensional localized correlated spectroscopy (2D L-COSY) at 7T is a highly-sensitive non-invasive technique for assessing brain metabolism. This study aims to assess tumor metabolism using 2D L-COSY at 7T for the detection of 2HG in IDH-mutant gliomas. Methods Nine treatment-naïve patients with suspected intracranial neoplasms were scanned at 7T MRI/MRS scanner using the 2D L-COSY technique. 2D-spectral processing and analyses were performed using a MATLAB-based reconstruction algorithm. Cross and diagonal peak volumes were quantified in the 2D L-COSY spectra and normalized with respect to the creatine peak at 3.0 ppm and quantified data were compared with previously-published data from six normal subjects. Detection of 2HG was validated using findings from immunohistochemical (IHC) staining in patients who subsequently underwent surgical resection. Results 2HG was detected in both of the IDH-mutated gliomas (grade III Anaplastic Astrocytoma and grade II Diffuse Astrocytoma) and was absent in IDH wild-type gliomas and in a patient with breast cancer metastases. 2D L-COSY was also able to resolve complex and overlapping resonances including phosphocholine (PC) from glycerophosphocholine (GPC), lactate (Lac) from lipids and glutamate (Glu) from glutamine (Gln). Conclusions This study demonstrates the ability of 2D L-COSY to unambiguously detect 2HG in addition to other neuro metabolites. These findings may aid in establishing 2HG as a biomarker of malignant progression as well as for disease monitoring in IDH-mutated gliomas.

Obesity-related conditions including heart disease, stroke, and type 2 diabetes are leading causes of preventable death. Recent evidence suggests that altered myocellular lipid metabolism in obesity may lead to increased insulin resistance (IR) that predisposes to these disorders. To test the hypothesis that muscles rich in type I vs. type II muscle fibers would exhibit similar changes in intramyocellular lipid (IMCL) and extramyocellular lipid (EMCL) content in obesity, we utilized a new four-dimensional multi echo echo-planar correlated spectroscopic imaging technique that allows separate determination of IMCL and EMCL content in individual calf muscles in obese vs. normal healthy human subjects. Calf muscles were scanned in 32 obese and 11 healthy subjects using a 3T MRI/MRS scanner, and IR in the obese subjects was documented by glucose tolerance testing. In obese subjects, elevation of both IMCL and EMCL content was observed in the gastrocnemius and tibialis anterior muscles (with mixed type I and II fiber content), while a significant increase in only IMCL content (+48%, p < 0.001) was observed in the soleus muscle (predominantly type I fibers). These observations indicate unexpected differences in changes in myolipid metabolism in type I vs. type II rich muscle regions in obesity, perhaps related to IR, and warrant further investigation.

Attempts have been made to reduce the total scan time in multi-dimensional J -resolved spectroscopic imaging (JRESI) using an echo-planar (EP) readout gradient, but acquisition duration remains a limitation for routine clinical use in the brain. We present here a significant acceleration achieved with a 4D EP-JRESI sequence that collects dual phase encoded lines within a single repetition time (TR) using two bipolar read-out trains. The performance and reliability of this novel 4D sequence, called Multi-Echo based Echo-Planar J -resolved Spectroscopic Imaging (ME-EP-JRESI), was evaluated in 10 healthy controls and a brain phantom using a 3 T MRI/MRS scanner. The prior knowledge fitting (ProFit) algorithm, with a new simulated basis set consisting of macromolecules and lipids apart from metabolites of interest, was used for quantitation. Both phantom and in - vivo data demonstrated that localization and spatial/spectral profiles of metabolites from the ME-EP-JRESI sequence were in good agreement with that of the EP-JRESI sequence. Both in the occipital and temporal lobe, metabolites with higher physiological concentrations including Glx (Glu+Gln), tNAA (NAA+NAAG), mI all had coefficient of variations between 9–25%. In summary, we have implemented, validated and tested the ME-EP-JRESI sequence, demonstrating that multi-echo acquisition can successfully reduce the total scan duration for EP-JRESI sequences.

Background: The frontal cortex, relevant to global cognition and motor function, is recruited to compensate for mobility dysfunction in older adults. However, the in vivo neurophysiological (e.g., neurometabolites) underpinnings of the frontal cortex compensation for mobility dysfunction remain poorly understood. The purpose of this study was to investigate the relationships among frontal cortex neurophysiology, mobility, and cognition in healthy older adults. Methods: Magnetic Resonance Spectroscopy (MRS) quantified N-acetylasparate (tNAA) and total choline (tCho) concentrations and ratios in the frontal cortex in 21 older adults. Four inertial sensors recorded the Timed Up & Go (TUG) test. Cognition was assessed using the Flanker Inhibitory Control and Attention Test which requires conflict resolution because of response interference from flanking distractors during incongruent trials. Congruent trials require no conflict resolution. Results: tNAA concentration significantly related to the standing (p = 0.04) and sitting (p = 0.03) lean angles. tCho concentration (p = 0.04) and tCho ratio (p = 0.02) significantly related to TUG duration. tCho concentration significantly related to incongruent response time (p = 0.01). tCho ratio significantly related to both congruent (p = 0.009) and incongruent (p < 0.001) response times. Congruent (p = 0.02) and incongruent (p = 0.02) Flanker response times significantly related to TUG duration. Conclusions: Altered levels of frontal cortex neurometabolites are associated with both mobility and cognitive abilities in healthy older adults. Identifying neurometabolites associated with frontal cortex compensation of mobility dysfunction could improve targeted therapies aimed at improving mobility in older adults.

A major goal of this pilot study was to quantify intramyocellular lipids (IMCL), extra-myocellular lipids (EMCL), unsaturation index (UI) and metabolites such as creatine (Cr), choline (Ch) and carnosine (Car), in the soleus muscle using two-dimensional (2D) localized correlated spectroscopy (L-COSY). Ten subjects with type 2 diabetes (T2D), controlled by lifestyle management alone, and 9 healthy control subjects, were studied. In T2D patients only, the following measurements were obtained: body mass index (BMI); waist circumference (WC); abdominal visceral and subcutaneous fat quantified using breath-held magnetic resonance imaging (MRI); a fasting blood draw for assessment of glucose, insulin, and estimation of homeostasis model assessment of insulin resistance (HOMA-IR), HbA1c, and high-sensitivity c-reactive protein (hs-CRP). Analysis of the soleus muscle 2D L-COSY spectral data showed significantly elevated IMCL ratios with respect to Cr and decreased IMCL UI in T2D when compared to healthy subjects (P < 0.05). In T2D subjects, Pearson correlation analysis showed a positive correlation of IMCL/Cr with EMCL/Cr (0.679, P < 0.05) and HOMA-IR (0.633, P < 0.05), and a non-significant correlation of visceral and subcutaneous fat with magnetic resonance spectroscopy (MRS) and other metrics. Characterization of muscle IMCL and EMCL ratios, UI, and abdominal fat, may be useful for the noninvasive assessment of the role of altered lipid metabolism in the pathophysiology of T2D, and for assessment of the effects of future therapeutic interventions designed to alter metabolic dysfunction in T2D.

Rajakumar Nagarajan1, Saadallah Ramadan2 and M. Albert Thomas11Department of Radiological Sciences, University of California, Los Angeles, CA 90095, USA. 2Department of Radiology, Brigham and Women Hospital, Boston, MA, 02115, USA. AbstractThe purpose of the study was to demonstrate the J-coupling connectivity network between the amide, aliphatic, and aromatic proton resonances of metabolites in human brain using two-dimensional (2D) localized correlated spectroscopy (L-COSY). Two different global water suppression techniques were combined with L-COSY, one before and another after localizing the volume of interest (VOI). Phantom solutions containing several cerebral metabolites at physiological concentrations were evaluated initially for sequence optimization. Nine healthy volunteers were scanned using a 3T whole body MRI scanner. The VOI for 2D L-COSY was placed in the right occipital white/gray matter region. The 2D cross and diagonal peak volumes were measured for several metabolites such as N-acetyl aspartate (NAA), creatine (Cr), free choline (Ch), glutamate/glutamine (Glx), aspartate (Asp), myo-inositol (mI), GABA, glutathione (GSH), phosphocholine (PCh), phosphoethanolamine (PE), tyrosine (Tyr), lactate (Lac), macromolecules (MM) and homocarnosine (Car). Using the pre-water suppression technique with L-COSY, the above mentioned metabolites were clearly identifiable and the relative ratios of metabolites were calculated. In addition to detecting multitude of aliphatic resonances in the high field region, we have demonstrated that the amide and aromatic resonances can also be detected using 2D L-COSY by pre water suppression more reliably than the post-water suppression.

Old age generally leads to smaller, weaker and slower skeletal muscles. To address the independent effects of weakness vs. slowing on fatigue in aging, we used a custom ergometer in a whole-body, 3 tesla magnetic resonance system to quantify knee extensor size, torque, velocity, power and intracellular energetics at baseline and during two 4-min fatiguing contraction protocols; one in which contraction velocity was constrained and torque varied (i.e., torque-dependent contractions; isokinetic, IsoK), and one in which torque was constrained and velocity varied (i.e., velocity-dependent contractions; isotonic, IsoT). On separate days, 10 young (27.5±1.2 yrs, 6 men) and 10 older (71.2±1.6 yrs, 5 men) healthy adults completed the IsoK (120°∙s-1, 0.5 Hz) and IsoT (20% maximal torque, 0.5 Hz) protocols, with continuous measures of intracellular [Pi], pH, and [H2PO4-]. At baseline, contractile volume (803.5±72.3 vs. 1,125.6±109.9cm3), specific IsoK torque (0.035±0.004 vs. 0.058±0.007Nm.cm-3) and IsoT velocity (121.4±11.6 vs. 176.3±8.0deg.s-1) were greater in young than older (p≤0.023). Fatigue (%initial specific torque) was greater in young than older for IsoK (40.1±3.0 vs. 61.2±5.3%, p=0.0028), and accompanied by greater [Pi] and [H2PO4-] and lower pH in the young (p≤0.001). For IsoT, fatigue (%initial velocity) was not different between groups (young: 56.5±5.5 vs. older: 47.2±4.9%, p=0.661), despite lower pH and greater [H2PO4-] in young than old (p≤0.001). Collectively, these results reveal that normalizing dynamometer outputs to assess age-related differences in fatigue obscures baseline differences in muscle weakness. Further, our results suggest the contractile machinery may be less sensitive to changes in pH in older than young.

Magnetic resonance spectroscopic imaging (MRSI) detects alterations in major prostate metabolites, such as citrate (Cit), creatine (Cr), and choline (Ch). We evaluated the sensitivity and accuracy of three-dimensional MRSI of prostate using an endorectal compared to an external phased array “receive” coil on a 3T MRI scanner. Eighteen patients with prostate cancer (PCa) who underwent endorectal MR imaging and proton (1H) MRSI were included in this study. Immediately after the endorectal MRSI scan, the PCa patients were scanned with the external phased array coil. The endorectal coil-detected metabolite ratio [(Ch+Cr)/Cit] was significantly higher in cancer locations (1.667 ± 0.663) compared to non-cancer locations (0.978 ± 0.420) (P < 0.001). Similarly, for the external phased array, the ratio was significantly higher in cancer locations (1.070 ± 0.525) compared to non-cancer locations (0.521 ± 0.310) (P < 0.001). The sensitivity and accuracy of cancer detection were 81% and 78% using the endorectal ‘receive’ coil, and 69% and 75%, respectively using the external phased array ‘receive’ coil.