Phosphorus Metabolites Research Articles

A Quantitative Comparison of 31P Magnetic Resonance Spectroscopy RF Coil Sensitivity and SNR between 7T and 10.5T Human MRI Scanners Using a Loop-Dipole 31P-1H Probe.

In vivo phosphorus-31 (31P) magnetic resonance spectroscopy (MRS) imaging (MRSI) is an important non-invasive imaging tool for studying cerebral energy metabolism, intracellular nicotinamide adenine dinucleotide (NAD) and redox ratio, and mitochondrial function. However, it is challenging to achieve high signal-to-noise ratio (SNR) 31P MRS/MRSI results owing to low phosphorus metabolites concentration and low phosphorous gyromagnetic ratio (γ). Many works have demonstrated that ultrahigh field (UHF) could significantly improve the 31P-MRS SNR. However, there is a lack of studies of the 31P MRSI SNR in the 10.5 Tesla (T) human scanner. In this study, we designed and constructed a novel 31P-1H dual-frequency loop-dipole probe that can operate at both 7T and 10.5T for a quantitative comparison of 31P MRSI SNR between the two magnetic fields, taking into account the RF coil B1 fields (RF coil receive and transmit fields) and relaxation times. We found that the SNR of the 31P MRS signal is 1.5 times higher at 10.5T as compared to 7T, and the power dependence of SNR on magnetic field strength (B0) is 1.9.

A birdcage transmit, 24-channel conformal receive array coil for sensitive 31P magnetic resonance spectroscopic imaging of the human brain at 7 T.

Phosphorus (31P) magnetic resonance spectroscopic imaging (MRSI) can serve as a critical tool for more direct quantification of brain energy metabolism, tissue pH, and cell membrane turnover. However, the low concentration of 31P metabolites in biological tissue may result in low signal-to-noise ratio (SNR) in 31P MRS images. In this work, we present an innovative design and construction of a 31P radiofrequency coil for whole-brain MRSI at 7 T. Our coil builds on current literature in ultra-high field 31P coil design and offers complete coverage of the brain, including the cerebellum and brainstem. The coil consists of an actively detunable volume transmit (Tx) resonator and a custom 24-channel receive (Rx) array. The volume Tx resonator is a 16-rung high-pass birdcage coil. The Rx coil consists of a 24-element phased array composed of catered loop shapes and sizes built onto a custom, close-fitting, head-shaped housing. The Rx array was designed to provide complete coverage of the head, while minimizing mutual coupling. The Rx configuration had a mean reflection coefficient better than -20 decibels (dB) when the coil was loaded with a human head. The mean mutual coupling ( ) among Rx elements, when loaded with a human head, was -16 dB. In phantom imaging, the phased array produced a central SNR that was 4.4-fold higher than the corresponding central SNR when operating the 31P birdcage as a transceiver. The peripheral SNR was 12-fold higher when applying the optimized phased array. In vivo 3D 31P MRSI experiments produced high-quality spectra in the cerebrum gray and white matter, as well as in the cerebellum. Characteristic phosphorus metabolites related to adenosine triphosphate metabolism and cell membrane turnover were distinguishable across all brain regions. In summary, our results demonstrate the potential of our novel coil for accurate, whole-brain 31P metabolite quantification.

Preliminary analysis of the THRIVE clinical trial on the effect of resistance exercise on skeletal muscle bioenergetics, strength and body composition in breast cancer survivors

Objective: Breast cancer survivors (BCS) are at high risk for loss in skeletal muscle mass, which can be exacerbated by cancer treatment and tumor related factors. While resistance exercise has been shown to be effective in improving strength and physical function in BCS, little is known as to how exercise modulates skeletal muscle bioenergetics in oncology populations. Uncovering these factors are critical for explaining adaptations to exercise among cancer survivors. Therefore, the objective of the THRIVE clinical trial is to determine the effects of resistance exercise training on modulating skeletal muscle bioenergetics in BCS. Hypothesis: We hypothesized that 12 weeks of resistance exercise would improve skeletal muscle bioenergetics, strength and body composition in BCS. Methodology: Preliminary analysis was performed on BCS (n=10; 45.7 ± 11.5 yr) who had completed chemotherapy within the previous 6 months and were recruited to complete 12 weeks of progressive, home-based resistance exercise program (3 supervised training bouts per week). Baseline and 12 weeks strength was assessed with isometric dynamometry and 1 rep max (RM) testing, body composition was measured with DEXA, and physical function was assessed with a 6 minute walk test. Changes in muscle bioenergetics, specifically changes in resting phosphorus metabolites, were assessed using 31-phosphorus magnetic resonance spectroscopy. In the original study design, participants were randomized to either receive creatinine supplement + exercise (n=5) or exercise alone (n=5); however, there were no significant differences between the interventions on the primary outcomes reported here, so the intervention groups were collapsed. Data: Handgrip strength, 1 RM chest press, 1 RM bicep curl, 1 RM leg press and 1 RM leg extension significantly increased (p<0.05) following 12 weeks of training in breast cancer survivors. Twelve weeks of resistance exercise training also significantly increased skeletal muscle phosphodiester (PDE) content and tended to increase total phosphocreatine and gammaATP. There were no significant changes in isometric knee strength, fat mass, lean mass, 6 minute walk testing distance or skeletal muscle inorganic phosphorous. Summary: This preliminary analysis indicates changes in strength and skeletal muscle bioenergetics occur in BCS following a 12-week home-based resistance exercise intervention. Further research is needed to validate these results. The ThriveWell Foundation, NIH (P30 CA054174 and P30 AG044271). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Postcontraction [acetylcarnitine] reflects interindividual variation in skeletal muscle ATP production patterns in vivo.

In addition to its role in substrate selection (carbohydrate vs. fat) for oxidative metabolism in muscle, acetylcarnitine production may be an important modulator of the energetic pathway by which ATP is produced. A combination of noninvasive magnetic resonance spectroscopy measures of cytosolic acetylcarnitine and ATP production pathways was used to investigate the link between [acetylcarnitine] and energy production in vivo. Intracellular metabolites were measured in the vastus lateralis muscle of eight males (mean: 28.4 yr, range: 25-35) during 8 min of incremental, dynamic contractions (0.5 Hz, 2-min stages at 6%, 9%, 12%, and 15% maximal torque) that increased [acetylcarnitine] approximately fivefold from resting levels. ATP production via oxidative phosphorylation, glycolysis, and the creatine kinase reaction was calculated based on phosphorus metabolites and pH. Spearman rank correlations indicated that postcontraction [acetylcarnitine] was positively associated with both absolute (mM) and relative (% total ATP) glycolytic ATP production (rs = 0.95, P = 0.001; rs = 0.93, P = 0.002), and negatively associated with relative (rs = -0.81, P = 0.02) but not absolute (rs = -0.14, P = 0.75) oxidative ATP production. Thus, acetylcarnitine accumulated more when there was a greater reliance on "nonoxidative" glycolysis and a relatively lower contribution from oxidative phosphorylation, reflecting the fate of pyruvate in working skeletal muscle. Furthermore, these data indicate striking interindividual variation in responses to the energy demand of submaximal contractions. Overall, the results of this preliminary study provide novel evidence of the coupling in vivo between ATP production pathways and the carnitine system.NEW & NOTEWORTHY Production of acetylcarnitine from acetyl-CoA and free carnitine may be important for energy pathway regulation in contracting skeletal muscle. Noninvasive magnetic resonance spectroscopy was used to investigate the link between acetylcarnitine and energy production in the vastus lateralis muscle during dynamic contractions (n = 8 individuals). A positive correlation between acetylcarnitine accumulation and "nonoxidative" glycolysis and an inverse relationship with oxidative phosphorylation, provides novel evidence of the coupling between ATP production and the carnitine system in vivo.

Labile Metabolite Profiling in Human Blood Using Phosphorus NMR Spectroscopy.

Phosphorus metabolites occupy a unique place in cellular function as critical intermediates and products of cellular metabolism. Human blood is the most widely used biospecimen in the clinic and in the metabolomics field, and hence an ability to profile phosphorus metabolites in blood, quantitatively, would benefit a wide variety of investigations of cellular functions in health and diseases. Mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy are the two premier analytical platforms used in the metabolomics field. However, detection and quantitation of phosphorus metabolites by MS can be challenging due to their lability, high polarity, structural isomerism, and interaction with chromatographic columns. The conventionally used 1H NMR, on the other hand, suffers from poor resolution of these compounds. As a remedy, 31P NMR promises an important alternative to both MS and 1H NMR. However, numerous challenges including the instability of phosphorus metabolites, their chemical shift sensitivity to solvent composition, pH, salt, and temperature, and the lack of identified metabolites have so far restricted the scope of 31P NMR. In the current study, we describe a method to analyze nearly 25 phosphorus metabolites in blood using a simple one-dimensional (1D) NMR spectrum. Establishment of the identity of unknown metabolites involved a combination of (a) comprehensively analyzing an array of 1D and two-dimensional (2D) 1H/31P homonuclear and heteronuclear NMR spectra of blood; (b) mapping the central carbon metabolic pathway; (c) developing and using 1H and 31P spectral and chemical shift databases; and finally (d) confirming the putative metabolite peaks with spiking using authentic compounds. The resulting simple 1D 31P NMR-based method offers an ability to visualize and quantify the levels of intermediates and products of multiple metabolic pathways, including central carbon metabolism, in one step. Overall, the findings represent a new dimension for blood metabolite analysis and are anticipated to greatly impact the blood metabolomics field.

Impact of cannabis use on brain metabolism using 31P and 1H magnetic resonance spectroscopy

PurposeThis prospective cross-sectional study investigated the influence of regular cannabis use on brain metabolism in young cannabis users by using combined proton and phosphorus magnetic resonance spectroscopy.MethodsThe study was performed in 45 young cannabis users aged 18–30, who had been using cannabis on a regular basis over a period of at least 2 years and in 47 age-matched controls. We acquired 31P MRS data in different brain regions at 3T with a double-resonant 1H/31P head coil, anatomic images, and 1H MRS data with a standard 20-channel 1H head coil. Absolute concentration values of proton metabolites were obtained via calibration from tissue water as an internal reference, whereas a standard solution of 75 mmol/l KH2PO4 was used as an external reference for the calibration of phosphorus signals.ResultsWe found an overall but not statistically significant lower concentration level of several proton and phosphorus metabolites in cannabis users compared to non-users. In particular, energy-related phosphates such as adenosine triphosphate (ATP) and inorganic phosphate (Pi) were reduced in all regions under investigation. Phosphocreatine (PCr) showed lowered values mainly in the left basal ganglia and the left frontal white matter.ConclusionThe results suggest that the increased risk of functional brain disorders observed in long-term cannabis users could be caused by an impairment of the energy metabolism of the brain, but this needs to be verified in future studies.

98-LB: Effects of SGLT2 Inhibition on Skeletal Muscle Bioenergetics and Myocellular Lipids in Patients with T2D and HFrEF

Background: The CV benefits of SGLT2i are well established. However, how skeletal muscle (SkM) bioenergetics respond to SGLT2i in T2D and HFrEF remains largely unknown. Objective: To explore the effects of empagliflozin on SkM bioenergetics (phosphorus metabolites & myocellular lipid content) at rest and post-exercise (31P & 1H MRS) and cardiac function (MRI). Methods: Subjects with T2D & HFrEF (<40%) (n=6) were randomized 2:1 to empagliflozin 25mg (SGLT2i) or placebo for 12 wks (Age=59±2.6, BMI=33.3±1.1, A1c=7.1±0.3, EF 28±4%). A cardiac MRI, & static/dynamic 31P & 1H SkM by MRS, were performed before & after treatment. Results: In the empagliflozin group, SkM 31P MRS at rest, showed decrease in phosphodiesterase [PDE]. 31P MRS post-exercise, showed significant improvement in Phosphocreatinine (PCr) recovery, expressed by the K value. 1H MRS showed a reduction of saturated intramyocellular lipids (IMCL-CH2:CH3 ratio). Conclusion: Empagliflozin in subjects with T2D and HFrEF had beneficial effects in SkM energy utilization and muscle recovery post-exercise as determined by a decrease in PDE and increase in K value. Additionally, empagliflozin decreased saturated IMCL, which could be expected to improve mitochondrial function and energy utilization. If similar findings were to occur in cardiac muscle, this could provide a novel mechanism for the beneficial CV effects of SGLT2i. Disclosure Y. Qin: None. N. D. Sanchez: None. A. Moody: None. F. M. Acosta: None. S. Neppala: None. M. Brown: None. H. Honka: None. L. A. Cruz Moreno: None. C. L. Triplitt: Speaker's Bureau; Novo Nordisk. G. D. Clarke: None. E. Cersosimo: None. R. A. DeFronzo: Speaker's Bureau; AstraZeneca. Advisory Panel; AstraZeneca, Bayer Inc., Boehringer-Ingelheim, Novo Nordisk. Research Support; AstraZeneca, Boehringer-Ingelheim, Merck & Co., Inc. C. Solis-Herrera: None. Funding Doris Duke Charitable Foundation; Voelcker Foundation; National Institutes of Health

In vivo phosphorus magnetic resonance spectroscopic imaging of the whole human liver at 7 T using a phosphorus whole-body transmit coil and 16-channel receive array: Repeatability and effects of principal component analysis-based denoising.

Quantitative three-dimensional (3D) imaging of phosphorus (31 P) metabolites is potentially a promising technique with which to assess the progression of liver disease and monitor therapy response. However, 31 P magnetic resonance spectroscopy has a low sensitivity and commonly used 31 P surface coils do not provide full coverage of the liver. This study aimed to overcome these limitations by using a 31 P whole-body transmit coil in combination with a 16-channel 31 P receive array at 7 T. Using this setup, we determined the repeatability of whole-liver 31 P magnetic resonance spectroscopic imaging (31 P MRSI) in healthy subjects and assessed the effects of principal component analysis (PCA)-based denoising on the repeatability parameters. In addition, spatial variations of 31 P metabolites within the liver were analyzed. 3D 31 P MRSI data of the liver were acquired with a nominal voxel size of 20 mm isotropic in 10 healthy volunteers twice on the same day. Data were reconstructed without denoising, and with PCA-based denoising before or after channel combination. From the test-retest data, repeatability parameters for metabolite level quantification were determined for 12 31 P metabolite signals. On average, 31 P MR spectra from 100 ± 25 voxels in the liver were analyzed. Only voxels with contamination from skeletal muscle or the gall bladder were excluded and no voxels were discarded based on (low) signal-to-noise ratio (SNR). Repeatability for most quantified 31 P metabolite levels in the liver was good to excellent, with an intrasubject variability below 10%. PCA-based denoising increased the SNR ~ 3-fold, but did not improve the repeatability for mean liver 31 P metabolite quantification with the fitting constraints used. Significant spatial heterogeneity of various 31 P metabolite levels within the liver was observed, with marked differences for the phosphomonoester and phosphodiester metabolites between the left and right lobe. In conclusion, using a 31 P whole-body transmit coil in combination with a 16-channel 31 P receive array at 7 T allowed 31 P MRSI acquisitions with full liver coverage and good to excellent repeatability.

Novel Sterically Crowded and Conformationally Constrained α-Aminophosphonates with a Near-Neutral pKa as Highly Accurate 31P NMR pH Probes. Application to Subtle pH Gradients Determination in Dictyostelium discoideum Cells.

In order to discover new 31P NMR markers for probing subtle pH changes (<0.2 pH unit) in biological environments, fifteen new conformationally constrained or sterically hindered α-aminophosphonates derived from diethyl(2-methylpyrrolidin-2-yl)phosphonate were synthesized and tested for their pH reporting and cytotoxic properties in vitro. All compounds showed near-neutral pKas (ranging 6.28–6.97), chemical shifts not overlapping those of phosphorus metabolites, and spectroscopic sensitivities (i.e., chemical shifts variation Δδab between the acidic and basic forms) ranging from 9.2–10.7 ppm, being fourfold larger than conventional endogenous markers such as inorganic phosphate. X-ray crystallographic studies combined with predictive empirical relationships and ab initio calculations addressed the inductive and stereochemical effects of substituents linked to the protonated amine function. Satisfactory correlations were established between pKas and both the 2D structure and pyramidalization at phosphorus, showing that steric crowding around the phosphorus is crucial for modulating Δδab. Finally, the hit 31P NMR pH probe 1b bearing an unsubstituted 1,3,2-dioxaphosphorinane ring, which is moderately lipophilic, nontoxic on A549 and NHLF cells, and showing pKa = 6.45 with Δδab = 10.64 ppm, allowed the first clear-cut evidence of trans-sarcolemmal pH gradients in normoxic Dictyostelium discoideum cells with an accuracy of <0.05 pH units.

Accumulation of Intramyocellular Acetylcarnitine is Associated with Glycolytic ATP Production In Vivo During Incremental Contractions in Human Skeletal Muscle

The interplay in vivo between muscle bioenergetics (ATP production) and intermediary metabolism in working skeletal muscle is not fully understood. During contractions, acetylcarnitine (AC) production may be an important modulator of energetic pathway and fuel selection for the support of ATP production. As contraction intensity and energetic demand increase, free carnitine in the mitochondria buffers excess acetyl‐CoA by converting it into AC and free CoA. This process enables greater flux of pyruvate into the mitochondria by lessening acetyl‐CoA’s product inhibition of pyruvate dehydrogenase. Further, as AC accumulates in the mitochondria, it will move into the cytosol, where by its conversion to malonyl‐CoA it can have the additional effect of inhibiting fatty acid translocation into the mitochondria. Here, a new method combining noninvasive magnetic resonance spectroscopic (MRS) measures of AC (by 1H MRS) with phosphorus MRS measures of ATP production was used to investigate the link between [AC] and energy production in vivo. Our primary aim was to test the novel hypothesis that AC accumulation during muscular work would be directly associated with nonoxidative (i.e., wherein the fate of pyruvate is lactate) glycolytic ATP production. Using a 3‐Tesla MR system with a dual‐tuned (1H/31P) surface coil, intracellular phosphorus metabolites and pH were measured in the vastus lateralis muscle of 8 males (mean 28.4 yr, range 25‐45) during 8 min of incremental isotonic contractions (0.5 Hz, 2‐min stages at 6, 9, 12, and 15% maximal torque). These metabolites and pH were then used to calculate ATP production (mM·s‐1) via oxidative phosphorylation, nonoxidative glycolysis, and the creatine kinase reaction (CK) throughout the contraction protocol. [AC] was measured in resting muscle pre‐ and post‐contractions. Spearman rank correlation coefficients (rs) were calculated to evaluate associations between post‐contraction [AC] and ATP production during the incremental protocol. On average, 13.1% (range 8.6 ‐ 17.3) of ATP production during the contraction protocol was from CK, 11.3% (0.4 ‐ 29.3) through glycolysis, and 75.6% (55.3 ‐ 90) by oxidative metabolism. [AC] increased &gt; 5‐fold, from 4.4 mM pre‐contractions (1.6‐11.6, n = 7) to 22.5 mM post (13.6 ‐ 33.8, n = 8; p = 0.004). Post‐contraction [AC] was positively correlated with absolute (mM·s‐1) and relative (% total) glycolytic ATP production (rs = 0.95, p = 0.001), supporting our primary hypothesis. Notably, post‐contraction [AC] was negatively correlated with relative (rs = ‐0.81 p = 0.02) but not absolute (rs = ‐0.14, p = 0.75) oxidative ATP production. Thus, cytosolic AC accumulated more when there was greater reliance on glycolysis and a relatively lower overall contribution from oxidative metabolism – a situation consistent with a buildup of acetyl‐CoA in the mitochondria. These results demonstrate, for the first time, the connection between energetic pathway selection and a key metabolic intermediate in working muscle in vivo. Intramyocellular AC may be a valuable tool for probing muscle energetics, substrate utilization, and metabolic flexibility in the future.

Accuracy and precision of 31P-MRS assessment for evaluating the effect of melatonin-pretreated mitochondria transferring on liver fibrosis of rats

This study examined the reliability of 31phosphorus-magnetic resonance spectroscopy (31P-MRS) to measure parameters of liver metabolic function in the intact animals. These parameters can help us to evaluate the severity and prognosis of liver fibrosis. In addition, 31P-MRS was also used to examine the protective effects of melatonin on liver mitochondria. An animal model of liver fibrosis was established via intraperitoneal administration of thioacetamide (TAA) to rats. Rats were scanned at baseline, week 3 and 6 after TAA treatment, respectively, to measure the longitudinal changes of phosphorus metabolite levels by 31P-MRS at 9.4 T. The results showed a consistent decline in the levels of phosphorus metabolites (inorganic phosphate, α-ATP, γ-ATP and NADH) in rats with fibrosis. Impaired mitochondrial respiration capacity, collagen accumulation and the extent of fibrosis in liver were markedly associated with decreased concentrations of phosphorus metabolites. Melatonin-pretreated mitochondria transferring efficiently prevented TAA-induced liver damage mainly by restoring mitochondrial function. In conclusion, the levels of phosphorus metabolites could serve as the indicators of mitochondrial oxidative capacity and thus provides a novel tool to evaluate mitochondrial integrity in the in vivo condition by using 31P-MRS in the setting of liver fibrosis.

Phosphonate production by marine microbes: Exploring new sources and potential function

SignificancePhosphonates are a class of phosphorus metabolites characterized by a highly stable C-P bond. Phosphonates accumulate to high concentrations in seawater, fuel a large fraction of marine methane production, and serve as a source of phosphorus to microbes inhabiting nutrient-limited regions of the oligotrophic ocean. Here, we show that 15% of all bacterioplankton in the surface ocean have genes phosphonate synthesis and that most belong to the abundant groups Prochlorococcus and SAR11. Genomic and chemical evidence suggests that phosphonates are incorporated into cell-surface phosphonoglycoproteins that may act to mitigate cell mortality by grazing and viral lysis. These results underscore the large global biogeochemical impact of relatively rare but highly expressed traits in numerically abundant groups of marine bacteria.

Relationship between brain iron deposition and mitochondrial dysfunction in idiopathic Parkinson\u2019s disease

BackgroundThe underlying pathophysiology of Parkinson's disease is complex, involving different molecular pathways, including brain iron deposition and mitochondrial dysfunction. At a molecular level, these disease mechanisms are likely interconnected. Therefore, they offer potential strategies for disease-modifying treatments. We aimed to investigate subcortical brain iron deposition as a potential predictor of the bioenergetic status in patients with idiopathic Parkinson’s disease.MethodsThirty patients with idiopathic Parkinson's disease underwent multimodal MR imaging (T1, susceptibility-weighted imaging, SWI) and 31phosphorus magnetic resonance spectroscopy imaging. SWI contrast-to-noise ratios served as a measure for brain iron deposition in the putamen, caudate, globus pallidus, and thalamus and were used in a multiple linear regression model to predict in-vivo energy metabolite ratios.ResultsSubcortical brain iron deposition, particularly in the putamen and globus pallidus, was highly predictive of the region-specific amount of high-energy-containing phosphorus metabolites in our subjects.ConclusionsOur study suggests that brain iron deposition but not the variability of individual volumetric measurements are highly predictive of mitochondrial impairment in vivo. These findings offer the opportunity, e.g., by using chelating therapies, to improve mitochondrial bioenergetics in patients with idiopathic Parkinson's disease.

31P solid-state NMR on skeletal muscle of wild and farmed Atlantic salmon

Over the past 50 years, 31P NMR has proven a powerful tool for obtaining information on cellular biochemistry. Here we use this technique for the first time to study intracellular phosphorous metabolites in skeletal muscle tissue of wild and farmed salmon, to investigate possible effects due to differences in diet and way of life. The wild salmon sample shows a significantly more diverse composition of metabolites compared to the farmed salmon sample. The differences are evident in the entire spectrum, including regions displaying resonances from phosphomonoesters and sugar phosphates, as well as other molecules important for phospholipid metabolism.It is demonstrated that 31P MAS NMR can be used to study a broad range of phosphorus metabolites ex vivo, which can give useful information, both on its own or as a supplement to other extraction-based analyses. Further 31P MAS NMR investigations on farmed salmon raised under different controlled conditions may give important insights into the broad array of health issues seen in farmed salmon.

Relationship of parieto‐occipital brain energy phosphate metabolism and cognition using 31P MRS at 7TESLA in preclinical stages of Alzheimer’s disease

AbstractBackgroundNeuroenergetics, a study of brain energy metabolism (BEM), may uncover cues for early disease biomarkers that potentially trigger downstream neuropathological changes in amnestic mild cognitive impairment (aMCI), a transitory stage of Alzheimer’s disease (AD). Advancements in brain imaging modalities, such as in vivo 31phosphorus magnetic resonance spectroscopy (31P MRS) at higher magnetic strength, offer promising platforms to measure energy and membrane phospholipid metabolites, a window to understand BEM. The primary goal was to quantify distinct features of phosphorus metabolites in parieto‐occipital lobes using 31P MRS at 7Tesla in aMCI. Another objective was to examine the clinical significance of the metabolites to brain‐behavior relationships. Specifically, we examined the correspondence across BEM and membrane phospholipid indices in parieto‐occipital regions of the brain with cognitive performance‐ executive functions (EF), memory, attention, and visuospatial skills.Methods19 aMCI participants enrolled in the study. Each participant completed a cognitive assessment and a scan using partial volume‐coil 31P MRS over parieto‐occipital lobes at 7Tesla. BEM indices were measured using three energy indicators: energy reserve (PCr/t‐ATP), energy consumption (intracellular_Pi/t‐ATP), and metabolic state (PCr/intracellular_Pi) along with regulatory co‐factors of BEM‐intracellular Mg2+ and pH; whereas the ratio of phosphomonoesters (PMEs) to phosphodiesters (PDEs) represented membrane phospholipid indicator.Results 31P MRS data over parieto‐occipital lobes showed thirteen well‐resolved peaks of the energy and membrane phospholipid metabolites at 7Tesla. The higher BEM indices were associated with lower cognitive performance of memory [(energy reserve indicator: CVLT p=0.004), (metabolic state indicator: CVLT p=0.007)], executive function [(metabolic state indicator: TOSL (p=0.044)], and attention [(pH: selective auditory task, p=0.044)]. The finding of higher brain energy indices in the parieto‐occipital lobes associated with lower cognition may represent compensatory hypermetabolism during the early stages of brain disturbances in aMCI.ConclusionThe critical contribution of this work was to develop and test a methodology to quantify neurometabolic markers of energy and membrane phospholipid metabolites at 7Tesla in aMCI. Additionally, the study findings implicated the role of BEM as an early neurometabolic marker of brain changes linked to cognitive decline in the preclinical stages of AD.

Early changes in hepatic energy metabolism and lipid content in recent-onset type 1 and 2 diabetes mellitus

Non-alcoholic fatty liver disease (NAFLD) is associated with abnormal mitochondrial capacity. While oxidative capacity can be increased in steatosis, hepatic ATP decreases in long-standing diabetes. However, longitudinal studies on diabetes-related NAFLD and its relationship to hepatic energy metabolism are lacking. This prospective study comprised volunteers with type 1 (T1DM, n= 30) and type 2 (T2DM, n= 37) diabetes. At diagnosis and 5 years later, we used 1H/31P magnetic resonance spectroscopy to measure hepatocellular lipid (HCL), γATP and inorganic phosphate (Pi) concentrations, and to assess adipose tissue volumes. Insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamps. At diagnosis, individuals with T2DM had higher HCL and adipose tissue volumes, but lower whole-body insulin sensitivity than those with T1DM, despite comparable glycemic control. NAFLD was present in 38% of individuals with T2DM and 7% with T1DM. After 5 years, visceral adipose tissue only increased in individuals with T2DM, while HCL almost doubled in this group (p <0.001), resulting in a 70% prevalence of NAFLD (independent of diabetes treatment). Changes in HCL correlated with adipose tissue volume and insulin resistance (r= 0.50 and r= 0.44, both p <0.05). Pi decreased by 17% and 10% in individuals with T2DM and T1DM (p <0.05), respectively. In T1DM, HCL did not change, whereas γATP decreased by 10% and correlated negatively with glycated hemoglobin (r= -0.56, p <0.05). The rapid increase in HCL during the early course of T2DM likely results from enlarging adipose tissue volume and insulin resistance in response to impaired hepatic mitochondrial adaptation. The decrease of phosphorus metabolites in T1DM may be due to pharmacological insulin supply. Previous studies suggested that the impaired function of mitochondria, the power plants of cells, can promote fatty liver and type 2 diabetes mellitus. This study now shows that during the first 5 years of type 2 diabetes the increase in body fat content rapidly leads to a doubling of liver fat content, whereas the energy metabolism of the patients' livers progressively declines. These data suggest that fat tissue mass and liver mitochondria have an important role in the development of fatty liver disease in humans with diabetes. NCT01055093.

Altered phospholipid and high-energy phosphate metabolism in the basal ganglia and thalamus of severe obsessive compulsive patients with treatment resistance: A phosphorus 31 nuclear magnetic resonance spectroscopy study.

Cerebral metabolism in obsessive-compulsive-disorder(OCD) has been the subject of numerous studies using proton magnetic resonance spectroscopy(MRS). Despite heterogeneous results, some studies have unraveled membrane turnover and energy metabolism abnormalities in different brain regions, suggesting that alterations in these processes may contribute to the pathophysiology. So far, no authors have explored phospholipids and high-energy phosphate metabolism using 31P-MRS, which allows in vivo quantification of phosphorus metabolites that are considered to be related to membrane turnover and energy metabolism. The aim of our study was to describe and compare brain metabolic changes using 31P-MRS in the striatum and the thalamus, between 23 severe OCD patients and 22 healthy controls. All subject underwent a clinical examination and a same 31P-MRS protocol. Significantly, increased concentrations of PC, PDE,PME,GPC,PME/PCr,PDE/PCr were found in patients compared to controls in the striatum and the thalamus. PCr and tATP were decreased in the striatum. Finally, significant correlations were found in the striatum and the thalamus between illness duration and some specific measured parameters. Our results showed significant modifications of the membrane and energy metabolism in the basal ganglia of severe OCD patients and suggests a link between energetic buffer and serotonin metabolism disorder.

Relationship of Parieto-Occipital Brain Energy Phosphate Metabolism and Cognition Using 31P MRS at 7-Tesla in Amnestic Mild Cognitive Impairment.

BackgroundThe human brain has high energy requirements that continuously support healthy neuronal activity and cognition. A disruption in brain energy metabolism (BEM) may contribute to early neuropathological changes such as accumulation of β-amyloid and tau in vulnerable populations. One such population is amnestic mild cognitive impairment (aMCI) where some individuals are at risk for developing dementia, i.e. Alzheimer’s disease (AD). Recent advances in imaging technology are providing new avenues to measure BEM accurately using 31phosphorus magnetic resonance spectroscopy (31P MRS) at ultra-high-field (UHF) magnetic strength 7-Tesla. This study investigates whether a methodology using partial volume-coil 31P MRS at 7T over parieto-occipital lobes can accurately quantify high-energy phosphate and membrane phospholipid metabolites in aMCI. A secondary objective was to explore BEM and membrane phospholipid indices’ correspondence with cognitive performance in domains of executive function (EF), memory, attention, and visuospatial skills in aMCI, a heterogeneous population.Methods19 aMCI participants enrolled in the study completed cognitive assessment and 31P MRS scan. BEM indices were measured using three energy indicators: energy reserve (PCr/t-ATP), energy consumption (intracellular_Pi/t-ATP), and metabolic state (PCr/intracellular_Pi) along with regulatory co-factors of BEM-intracellular Mg2 + and pH; whereas the ratio of phosphomonoesters (PMEs) to phosphodiesters (PDEs) – membrane phospholipid indicator.Results31P MRS scan showed thirteen well-resolved peaks with precise quantification of the phosphorus metabolites at UHF. The higher BEM indices were associated with lower cognitive performance of memory [(energy reserve indicator: CVLT p = 0.004), (metabolic state indicator: CVLT p = 0.007)], executive function [(metabolic state indicator: TOSL (p = 0.044)], and attention [(pH: selective auditory task, p = 0.044)]. The finding of an inverse relationship observed in the parieto-occipital lobes suggests an association between neuronal energy markers with cognition in aMCI.ConclusionThe significant contribution of this preliminary research was to establish the feasibility of utilizing a methodology at UHF to accurately measure high-energy phosphate and membrane phospholipid metabolites in a population with heterogeneous outcomes. This work offers a novel approach for future work to further elucidate early dementia biomarkers or precursors to the downstream accumulation of amyloid and tau using the combination of MRS-PET imaging modalities in AD.

Mineral Intake and Clinical Symptoms in Adult Patients with Hypophosphatasia.

Hypophosphatasia (HPP) is a rare inherited metabolic disorder characterized by deficient activity of the tissue-nonspecific alkaline phosphatase entailing impaired turnover of phosphorus metabolites. Dietary mineral intake is suspected to influence clinical symptoms of HPP, but scientific evidence is missing. Cross-sectional matched-pairs study collecting comprehensive data on nutrient intake in 20 HPP patients and 20 unaffected, age- and gender-matched controls. Dietary information and clinical symptoms were documented in detail over 7 consecutive days using structured diaries. Baseline data and type of energy-supplying nutrients were balanced between both groups. Median nutritional intake of phosphorus and calcium were significantly lower in HPP patients versus controls, which is partially attributable to lower energy consumption in HPP patients. Differences regarding phosphorus and calcium (Ca/P) ratio and uptake of magnesium, zinc, and vitamin B6 were not statistically significant. Both high (≥ 1375 mg/d) and low intakes (< 1100 mg/d) of phosphorus were significantly associated with an increased frequency of neuropsychiatric symptoms (P = 0.02). Similarly, very high and very low intake of calcium was significantly associated with musculoskeletal (P < 0.01), gastrointestinal (P = 0.02), and neuropsychiatric (P < 0.001) symptoms. An increased Ca/P ratio was associated with increased tiredness/fatigue (P < 0.01), whereas a decreased Ca/P was associated with gastrointestinal issues (P = 0.01). Phosphorus and calcium intake seem reduced in HPP patients along with reduced total energy consumption. Particularly high as well as very low absolute or unbalanced phosphorus and calcium intake are associated with an increased frequency of clinical symptoms.

129-OR: Abnormal Mitochondrial Activity in Pain Processing Regions of the Brain in Painful Diabetic Peripheral Neuropathy

Aims: The management of painful diabetic peripheral neuropathy (pDPN) is inadequate because the disease mechanisms are not fully understood. We assessed cerebral cellular bioenergetics using phosphorus magnetic resonance spectroscopy (31P-MRS) to determine whether high energy phosphate metabolite levels are altered in the pain processing regions of the brain in pDPN. Methods: A total of 66 subjects, 44 with type 2 diabetes (12 no-DPN, 13 painless-DPN and 19 pDPN) and 12 healthy volunteers (HV), underwent detailed clinical and neurophysiological assessments, and 31P-MRS brain imaging at 3-Tesla (Ingenia, Phillips Healthcare) with voxels placed over the right somatosensory cortex and the thalamus (TR 4s, TR 0.26ms, voxel size 21 x 21 x 40mm3). Measures reflecting cellular bioenergetics (mitochondrial function), ATP to phosphocreatine (PCr) and inorganic phosphate (Pi) ratios (ATP:PCr and ATP:Pi) were calculated. Results: There was a significant group effect in the ATP:PCr ratio at the thalamus (p=0.016) and somatosensory cortex (p=0.025). The ATP:PCr at the thalamus was significantly higher in the pDPN group (0.50±0.06) compared to HV (0.44±0.04, p=0.024) and no-DPN (0.42±0.07, p=0.006). Moreover, the ATP:PCr ratio at the somatosensory cortex was significantly higher in pDPN (0.48 ±0.1) compared to HV (0.38 ±0.1, p=0.035). In addition, the ratio correlated with the numeric pain score ratings during the MRI scan at both brain regions. Conclusions: This is the first study to use 31P-MRS to study cerebral energetics in human-DPN and peripheral painful neuropathies. We demonstrated significantly higher ATP:PCr ratios in patients with pDPN in the somatosensory cortex and thalamus, which correlated with pain severity. This is suggestive of increased cellular energy usage in pain processing regions of the brain, perhaps due to continuous nociceptive inputs. Altered cerebral phosphorus metabolite ratios may serve as a biomarker of neuropathic pain in diabetes. Disclosure G.P. Sloan: None. A. Anton: None. D. Selvarajah: None. S. Tesfaye: Advisory Panel; Self; Mitsubishi Tanabe Pharma Corporation, Wörwag Pharma. Speaker’s Bureau; Self; Abbott, AstraZeneca, Grunenthal Group, Napp Pharmaceuticals, Novo Nordisk Inc., Pfizer Inc. I.D. Wilkinson: None.