Clinical trials involving patients with Duchenne muscular dystrophy are hindered by the lack of suitable objective end points. The purpose of this study was to examine whether muscle lipid ...infiltration measured with the three-point Dixon MRI technique has value as a marker of disease severity.
Disease severity in nine boys (mean age, 8.6 +/- 2.7 years) with Duchenne muscular dystrophy was determined with the functional ability scale of Brooke and associates. Functional scores were compared with strength measurements obtained by manual testing of muscles of the lower extremities, knee extensor strength measured with an isokinetic dynamometer, and muscle fat percentage in the quadriceps and hamstrings determined with the three-point Dixon MRI technique.
MRI measurements of fat infiltration had stronger correlation (p < 0.05) with functional grade than did measurements obtained with manual muscle testing (p = 0.07) or quantitative strength measured with the isokinetic dynamometer (p = 0.54). Muscle fat percentage did not correlate with strength measurements from manual or dynamometer muscle testing but increased with age in subjects with Duchenne muscular dystrophy.
Muscle adiposity values obtained with three-point Dixon MRI are accurate in assessment of disease severity in patients with Duchenne muscular dystrophy. Because they are not influenced by patient effort or examiner variability, these measurements are more objective and reproducible than measurements of muscle strength.
Childhood posterior fossa group A ependymomas (PFAs) have limited treatment options and bear dismal prognoses compared to group B ependymomas (PFBs). PFAs overexpress the oncohistone-like protein ...EZHIP (enhancer of Zeste homologs inhibitory protein), causing global reduction of repressive histone H3 lysine 27 trimethylation (H3K27me3), similar to the oncohistone H3K27M. Integrated metabolic analyses in patient-derived cells and tumors, single-cell RNA sequencing of tumors, and noninvasive metabolic imaging in patients demonstrated enhanced glycolysis and tricarboxylic acid (TCA) cycle metabolism in PFAs. Furthermore, high glycolytic gene expression in PFAs was associated with a poor outcome. PFAs demonstrated high EZHIP expression associated with poor prognosis and elevated activating mark histone H3 lysine 27 acetylation (H3K27ac). Genomic H3K27ac was enriched in PFAs at key glycolytic and TCA cycle–related genes including
and
. Similarly, mouse neuronal stem cells (NSCs) expressing wild-type EZHIP (EZHIP-WT) versus catalytically attenuated EZHIP-M406K demonstrated H3K27ac enrichment at
and
, accompanied by enhanced glycolysis and TCA cycle metabolism.
α
, a key component of the metabolic regulator AMP-activated protein kinase (AMPK), also showed H3K27ac enrichment in PFAs and EZHIP-WT NSCs. The AMPK activator metformin lowered EZHIP protein concentrations, increased H3K27me3, suppressed TCA cycle metabolism, and showed therapeutic efficacy in vitro and in vivo in patient-derived PFA xenografts in mice. Our data indicate that PFAs and EZHIP-WT–expressing NSCs are characterized by enhanced glycolysis and TCA cycle metabolism. Repurposing the antidiabetic drug metformin lowered pathogenic EZHIP, increased H3K27me3, and suppressed tumor growth, suggesting that targeting integrated metabolic/epigenetic pathways is a potential therapeutic strategy for treating childhood ependymomas.
Cortical bone is strongly and inversely related to the percent marrow fat along the femoral shaft regardless of age, gender, or anthropometric measures.
Objective:
Recent studies suggest a close ...local link between bone marrow adiposity and endosteal bone formation. Using magnetic resonance imaging, we examined whether the relation between the amount of marrow fat and cortical bone is present at multiple sites along the diaphyses of the long bones of young and old males and females.
Design:
The relations between values for cortical bone area and percent marrow fat in each 5-mm section along the midthird of both femoral shafts were determined using magnetic resonance imaging in eight healthy young (aged <25 yr), and nine healthy old (aged >55 yr) men and women.
Results:
Strong inverse correlations were observed between values for cortical bone area and percent marrow fat along the shafts of all 34 femurs; r values between −0.54 to −0.97; all P values = 0.01–0.0001. The strength of this local association was comparable in the young and the elderly and in males and females.
Conclusion:
Our results underscore the strength of the local connections between bone and marrow adiposity. Increasing our understanding of the mechanism for this association could lead to better diagnosis and treatment approaches for osteoporosis.
Diffuse intrinsic pontine gliomas (DIPG) are highly aggressive tumors with no currently available curative therapy. This study evaluated whether measurements of in vivo cell metabolites using ...magnetic resonance spectroscopy (MRS) may serve as biomarkers of response to therapy, including progression.
Single-voxel MR spectra were serially acquired in two cohorts of patients with DIPG treated with radiation therapy (RT) with or without concurrent chemotherapy and prior to progression: 14 participants were enrolled in a clinical trial of adjuvant glioma-associated antigen peptide vaccines and 32 patients were enrolled who did not receive adjuvant vaccine therapy. Spearman correlations measured overall survival associations with absolute metabolite concentrations of myo-inositol (mI), creatine (Cr), and
-acetyl-aspartate (NAA) and their ratios relative to choline (Cho) during three specified time periods following completion of RT. Linear mixed-effects regression models evaluated the longitudinal associations between metabolite ratios and time from death (terminal decline).
Overall survival was not associated with metabolite ratios obtained shortly after RT (1.9-3.8 months post-diagnosis) in either cohort. In the vaccine cohort, an elevated mI/Cho ratio after 2-3 doses (3.9-5.2 months post-diagnosis) was associated with longer survival (rho = 0.92, 95% CI 0.67-0.98). Scans performed up to 6 months before death showed a terminal decline in the mI/Cho ratio, with an average of 0.37 ratio/month in vaccine patients (95% CI 0.11-0.63) and 0.26 (0.04-0.48) in the non-vaccine cohort.
Higher mI/Cho ratios following RT, consistent with less proliferate tumors and decreased cell turnover, were associated with longer survival, suggesting that this ratio can serve as a biomarker of prognosis following RT. This finding was seen in both cohorts, although the association with OS was detected earlier in the vaccine cohort. Increased mI/Cho (possibly reflecting immune-effector cell influx into the tumor as a mechanism of tumor response) requires further study.
Objective To determine associations between patient and clinical factors with postnatal brain metabolism in term neonates with congenital heart disease (CHD) via the use of quantitative magnetic ...resonance spectroscopy. Study design Neonates with CHD were enrolled prospectively to undergo pre- and postoperative 3T brain magnetic resonance imaging. Short-echo single-voxel magnetic resonance spectroscopy of parietal white matter was used to quantify metabolites related to brain maturation (n-acetyl aspartate, choline, myo- inositol), neurotransmitters (glutamate and gamma-aminobutyric acid), energy metabolism (glutamine, citrate, glucose, and phosphocreatine), and injury/apoptosis (lactate and lipids). Multivariable regression was performed to search for associations between (1) patient-specific/prenatal/preoperative factors with concurrent brain metabolism and (2) intraoperative and postoperative factors with postoperative brain metabolism. Results A total of 83 magnetic resonance images were obtained on 55 subjects. No patient-specific, prenatal, or preoperative factors associated with concurrent metabolic brain dysmaturation or elevated lactate could be identified. Chromosome 22q11 microdeletion and age at surgery were predictive of altered concurrent white matter phosphocreatine ( P < .0055). The only significant intraoperative association found was increased deep hypothermic circulatory arrest time with reduced postoperative white matter glutamate and gamma-aminobutyric acid ( P < .0072). Multiple postoperative factors, including increased number of extracorporeal membrane oxygenation days ( P < .0067), intensive care unit, length of stay ( P < .0047), seizures in the intensive care unit ( P < .0009), and home antiepileptic use ( P < .0002), were associated with reduced postoperative white matter n-acetyl aspartate. Conclusion Multiple postoperative factors were found to be associated with altered brain metabolism in term infants with CHD, but not patient-specific, preoperative, or intraoperative factors.
Objective To noninvasively determine brain temperature of neonates with hypoxic-ischemic encephalopathy (HIE) during and after therapeutic hypothermia. Study design Using a phantom, we derived a ...calibration curve to calculate brain temperature based on chemical shift differences in magnetic resonance spectroscopy. We enrolled infants admitted for therapeutic hypothermia and assigned them to a moderate HIE (M-HIE) or severe HIE (S-HIE) group based on Sarnat staging. Rectal (core) temperature and magnetic resonance spectroscopy data used to derive regional brain temperatures (basal ganglia, thalamus, and cortical gray matter) were acquired concomitantly during and after therapeutic hypothermia. We compared brain and rectal temperature in the M-HIE and S-HIE groups during and after therapeutic hypothermia using 2-tailed t -tests. Results Eighteen patients (14 with M-HIE and 4 with S-HIE) were enrolled. As expected, both brain and rectal temperatures were lower during therapeutic hypothermia than after therapeutic hypothermia. Brain temperature in patients with S-HIE was higher than in those with M-HIE both during (35.1 ± 1.3°C vs 33.7 ± 1.2°C; P < .01) and after therapeutic hypothermia (38.1 ± 1.5°C vs 36.8 ± 1.3°C; P < .01). The brain–rectal temperature gradient was also greater in the S-HIE group both during and after therapeutic hypothermia. Conclusion For this analysis of a small number of patients, brain temperature and brain–rectal temperature gradient were higher in neonates with S-HIE than in those with M-HIE during and after therapeutic hypothermia. Further studies are needed to determine whether further decreasing brain temperature in neonates with S-HIE is safe and effective in improving outcome.
Extracorporeal membrane oxygenation (ECMO) is an effective therapy for supporting infants with reversible cardiopulmonary failure. Still, survivors are at risk for long-term neurodevelopmental ...impairments, the cause of which is not fully understood.
To elucidate the effects of ECMO on the newborn brain. We hypothesized that the cerebral metabolic profile of neonates who received ECMO would differ from neonates who did not receive ECMO. To address this, we used magnetic resonance spectroscopy (1H-MRS) to investigate the effects of venoarterial and venovenous ECMO on cerebral metabolism.
41 neonates treated with ECMO were contrasted to 38 age-matched neonates.
All 1H-MRS data were acquired from standardized grey matter and white matter regions of interest using a short-echo (TE = 35 milliseconds), point-resolved spectroscopy sequence (PRESS) and quantitated using LCModel. Metabolite concentrations (mmol/kg) were compared across groups using multivariate analysis of covariance. Elevated creatine (p = 0.002) and choline (p = 0.005) concentrations were observed in the grey matter among neonates treated with ECMO relative to the reference group. Likewise, choline concentrations were elevated in the white matter (p = 0.003) while glutamate was reduced (p = 0.03). Contrasts between ECMO groups revealed lower osmolite concentrations (e.g. myoinositol) among the venovenous ECMO group.
Neonates who underwent ECMO were found to have an abnormal cerebral metabolic profile, with the pattern of abnormalities suggestive of an underlying inflammatory process. Additionally, neonates who underwent venovenous ECMO had low cerebral osmolite concentrations as seen in vasogenic edema.
H3K27M diffuse intrinsic pontine gliomas (DIPGs) are fatal and lack treatments. They mainly harbor H3.3K27M mutations resulting in H3K27me3 reduction. Integrated analysis in H3.3K27M cells, tumors, ...and in vivo imaging in patients showed enhanced glycolysis, glutaminolysis, and tricarboxylic acid cycle metabolism with high alpha-ketoglutarate (α-KG) production. Glucose and/or glutamine-derived α-KG maintained low H3K27me3 in H3.3K27M cells, and inhibition of key enzymes in glycolysis or glutaminolysis increased H3K27me3, altered chromatin accessibility, and prolonged survival in animal models. Previous studies have shown that mutant isocitrate-dehydrogenase (mIDH)1/2 glioma cells convert α-KG to D-2-hydroxyglutarate (D-2HG) to increase H3K27me3. Here, we show that H3K27M and IDH1 mutations are mutually exclusive and experimentally synthetic lethal. Overall, we demonstrate that H3.3K27M and mIDH1 hijack a conserved and critical metabolic pathway in opposing ways to maintain their preferred epigenetic state. Consequently, interruption of this metabolic/epigenetic pathway showed potent efficacy in preclinical models, suggesting key therapeutic targets for much needed treatments.
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•H3.3K27M mutations enhance glucose, glutamine, and TCA cycle metabolism•TCA cycle intermediate α-KG enables maintenance of H3K27 hypomethylation•Targeting enzymes related to α-KG synthesis including WT-IDH1 and/or GDH is therapeutic•H3.3K27M and mutant-IDH1 in gliomas are mutually exclusive and are synthetic lethal
Chung et al. show that H3.3K27M mutation in DIPGs enhances glycolysis and TCA cycle metabolism to produce α-KG that is required to maintain a preferred epigenetic state of low H3K27me3. Inhibiting enzymes related to α-KG production increases H3K27me3 and results in anti-tumor activity in mouse models of DIPG.
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