Changes in Brain Energy and Membrane Metabolism in Glioblastoma following Chemoradiation

Brain parenchyma infiltration with glioblastoma (GB) cannot be entirely visualized by conventional magnetic resonance imaging (MRI). The aim of this study was to investigate changes in the energy and membrane metabolism measured with phosphorous MR spectroscopy (31P-MRS) in the presumably “normal-appearing” brain following chemoradiation therapy (CRT) in GB patients in comparison to healthy controls. Twenty (seven female, thirteen male) GB patients underwent a 31P-MRS scan prior to surgery (baseline) and after three months of standard CRT (follow-up examination. The regions of interest “contrast-enhancing (CE) tumor” (if present), “adjacent to the (former) tumor”, “ipsilateral distant” hemisphere, and “contralateral” hemisphere were compared, differentiating between patients with stable (SD) and progressive disease (PD). Metabolite ratios PCr/ATP, Pi/ATP, PCr/Pi, PME/PDE, PME/PCr, and PDE/ATP were investigated. In PD, energy and membrane metabolism in CE tumor areas have a tendency to “normalize” under therapy. In different “normal-appearing” brain areas of GB patients, the energy and membrane metabolism either “normalized” or were “disturbed”, in comparison to baseline or controls. Differences were also detected between patients with SD and PD. 31P-MRS might contribute as an additional imaging biomarker for outcome measurement, which remains to be investigated in a larger cohort.

Cardiac energetics alteration in a chronic hypoxia rat model: A non-invasive in vivo 31P magnetic resonance spectroscopy study

BACKGROUND: Energetics alteration plays a crucial role in the myocardial injury process in chronic hypoxia diseases (CHD). 31P magnetic resonance spectroscopy (MRS) can investigate alterations in cardiac energetics in vivo. OBJECTIVE: To characterize the potential value of 31P MRS in evaluating cardiac energetics alteration of chronic hypoxic rats (CHRs). METHODS: Twenty-four CHRs were induced by SU5416 combined with hypoxia and divided into four groups according to the modeling time of one, two, three and five weeks, respectively. Control group also contains six rats. 31P MRS was performed weekly and the ratio of concentrations of phosphocreatine (PCr) to adenosine triphosphate (ATP) (PCr/ATP) was obtained. In addition, the cardiac structure index and systolic function parameters, including the right ventricular ejection fraction (RVEF), right ventricular end-diastolic volume index (RVEDVi), right ventricular end-systolic volume index (RVESVi), and the left ventricular function parameters, were measured. RESULTS: Decreased resting cardiac PCr/ATP ratio in CHRs was observed at the first week, compared to the control group (2.90±0.35 vs. 3.31±0.45, p = 0.045), while the RVEF, RVEDVi, and RVESVi decreased at the second week (p < 0.05). The PCr/ATP ratio displayed a significant correlation with RVEF (r = 0.605, p = 0.001), RVEDVi, and RVESVi (r = –0.661, r = –0.703; p < 0.001). CONCLUSIONS: 31P MRS can easily detect the cardiac energetics alteration in a CHR model before the onset of ventricular dysfunction. The decreased PCr/ATP ratio likely reveales myocardial injury and cardiac dysfunction.

Mechanistic insights from a multiparametric magnetic resonance imaging study regarding the role of sodium glucose co-transporter 2 inhibitors

Background Type 2 diabetes (T2D) is associated with an increased risk of heart failure (HF) and cardiovascular (CV) mortality. Sodium–glucose-co transporter-2 (SGLT2) inhibitors reduce the risk of major adverse CV events and hospitalisation for HF in T2D patients with high cardiovascular risk, despite only a modest improvement in glycemic control. Restoring cellular energy homeostasis and reversing adverse cardiac remodelling in diabetes have been speculated as a potential metabolic modulatory effect of SGLT2 inhibitors leading to their beneficial CV outcomes. Myocardial energy deficient states can be detected non-invasively by 31-phosphorus magnetic resonance spectroscopy (31P-MRS). Objectives Utilising cardiovascular magnetic resonance imaging (CMR) and 31P-MRS in a single centre longitudinal cohort study, we aimed to investigate the effects of the selective SGLT2 inhibitor empagliflozin on myocardial energetics, function, perfusion, and myocardial cellular volume in patients with T2D. Methods Eighteen consecutive T2D patients who were commenced on empagliflozin in cardiometabolic optimisation clinics underwent CMR and 31P-MRS scans before and after twelve-week empagliflozin treatment, and plasma N-terminal pro hormone B-type natriuretic peptide (NT-proBNP) levels were measured. Ten controls with no diabetes underwent an identical 31P-MRS and CMR protocol on a single visit. Results When compared to controls, patients with T2D showed: lower myocardial energetics (1.52±0.40 vs 2.20±0.5, p=0.0005), lower stress myocardial blood flow (1.60±0.50 vs 2.10±0.50, p=0.02) and lower left ventricular ejection fraction (52±13% vs 63±4%, p=0.01). Treatment with empagliflozin led to significant improvements in myocardial energetics (PCr/ATP: 1.52 to 1.76, p=0.009). This was accompanied by a relative 13% improvement in left ventricular ejection fraction (p=0.001), 3% improvement in global longitudinal strain (p=0.01), 61% reduction in NTproBNP (p=0.05), and 9% reduction in myocardial cell volume (p=0.04). No significant change in myocardial blood flow or diastolic strain was detected. Conclusions For the first time, we demonstrate that empagliflizon improves myocardial energetics and function, reduces myocardial cellular volume, and reduces NT-proBNP levels in patients with T2D. FUNDunding Acknowledgement Type of funding sources: Foundation. Main funding source(s): British Heart Foundation PCr/ATP LVEF

Phosphorous Magnetic Resonance Spectroscopy to Detect Regional Differences of Energy and Membrane Metabolism in Naïve Glioblastoma Multiforme

Background: Glioblastoma multiforme (GBM) is a highly malignant primary brain tumor with infiltration of, on conventional imaging, normal-appearing brain parenchyma. Phosphorus magnetic resonance spectroscopy (31P-MRS) enables the investigation of different energy and membrane metabolites. The aim of this study is to investigate regional differences of 31P-metabolites in GBM brains. Methods: In this study, we investigated 32 patients (13 female and 19 male; mean age 63 years) with naïve GBM using 31P-MRS and conventional MRI. Contrast-enhancing (CE), T2-hyperintense, adjacent and distant ipsilateral areas of the contralateral brain and the brains of age- and gender-matched healthy volunteers were assessed. Moreover, the 31P-MRS results were correlated with quantitative diffusion parameters. Results: Several metabolite ratios between the energy-dependent metabolites and/or the membrane metabolites differed significantly between the CE areas, the T2-hyperintense areas, the more distant areas, and even the brains of healthy volunteers. pH values and Mg2+ concentrations were highest in visible tumor areas and decreased with distance from them. These results are in accordance with the literature and correlated with quantitative diffusion parameters. Conclusions: This pilot study shows that 31P-MRS is feasible to show regional differences of energy and membrane metabolism in brains with naïve GBM, particularly between the different “normal-appearing” regions and between the contralateral hemisphere and healthy controls. Differences between various genetic mutations or clinical applicability for follow-up monitoring have to be assessed in a larger cohort.

Utilizing Dynamic Phosphorous-31 Magnetic Resonance Spectroscopy for the Early Detection of Acute Compartment Syndrome: A Pilot Study on Rats

Introduction: Disasters, including terrorism and earthquakes, are significant threats to people and may lead to many people requiring rescue. The longer the rescue takes, the higher the chances of an individual contracting acute compartment syndrome (ACS). ACS is fatal if diagnosed too late, and early diagnosis and treatment are essential. Objective: To assess the ability of dynamic phosphorus magnetic resonance spectroscopy (31P-MRS) in the early detection of muscular damage in ACS. Materials and Methods: Six ACS model rats were used for serial 31P-MRS scanning (9.4 Tesla). Skeletal muscle metabolism, represented by the levels of phosphocreatine (PCr), inorganic phosphate (Pi), and adenosine triphosphate (ATP), was assessed. The PCr/(Pi + PCr) ratio, which decreases with ischemia, was compared with simultaneously sampled plasma creatine phosphokinase (CPK), a muscle damage marker. Results: The PCr/(Pi + PCr) ratio significantly decreased after inducing ischemia (from 0.86 ± 0.10 to 0.18 ± 0.06; p < 0.05), while CPK did not change significantly (from 89 ± 29.46 to 241.50 ± 113.28; p > 0.05). The intracellular and arterial pH index decreased over time, revealing significant differences at 120 min post-ischemia (from 7.09 ± 0.01 to 6.43 ± 0.13, and from 7.47 ± 0.03 to 7.39 ± 0.04, respectively). In the reperfusion state, the spectra and pH did not return to the original values. Conclusions: The dynamic 31P-MRS technique can rapidly detect changes in muscle bioenergetics. This technique is a promising non-invasive method for determining early muscular damage in ACS.

Quantitative Assessment of Occipital Metabolic and Energetic Changes in Parkinson’s Patients, Using In Vivo 31P MRS-Based Metabolic Imaging at 7T

Abnormal energy metabolism associated with mitochondrial dysfunction is thought to be a major contributor to the progression of neurodegenerative diseases such as Parkinson’s disease (PD). Recent advancements in the field of magnetic resonance (MR) based metabolic imaging provide state-of-the-art technologies for non-invasively probing cerebral energy metabolism under various brain conditions. In this proof-of-principle clinical study, we employed quantitative 31P MR spectroscopy (MRS) imaging techniques to determine a constellation of metabolic and bioenergetic parameters, including cerebral adenosine triphosphate (ATP) and other phosphorous metabolite concentrations, intracellular pH and nicotinamide adenine dinucleotide (NAD) redox ratio, and ATP production rates in the occipital lobe of cognitive-normal PD patients, and then we compared them with age-sex matched healthy controls. Small but statistically significant differences in intracellular pH, NAD and ATP contents and ATPase enzyme activity between the two groups were detected, suggesting that subtle defects in energy metabolism and mitochondrial function are quantifiable before regional neurological deficits or pathogenesis begin to occur in these patients. Pilot data aiming to evaluate the bioenergetic effect of mitochondrial-protective bile acid, ursodeoxycholic acid (UDCA) were also obtained. These results collectively demonstrated that in vivo 31P MRS-based neuroimaging can non-invasively and quantitatively assess key metabolic-energetic metrics in the human brain. This provides an exciting opportunity to better understand neurodegenerative diseases, their progression and response to treatment.