Neural-network classification of cardiac disease from 31P cardiovascular magnetic resonance spectroscopy measures of creatine kinase energy metabolism.

BACKGROUND: The heart's energy demand per gram of tissue is the body's highest and creatine kinase (CK) metabolism, its primary energy reserve, is compromised in common heart diseases. Here, neural-network analysis is used to test whether noninvasive phosphorus (31P) cardiovascular magnetic resonance spectroscopy (CMRS) measurements of cardiac adenosine triphosphate (ATP) energy, phosphocreatine (PCr), the first-order CK reaction rate kf, and the rate of ATP synthesis through CK (CK flux), can predict specific human heart disease and clinical severity. METHODS: The data comprised the extant 178 complete sets of PCr and ATP concentrations, kf, and CK flux data from human CMRS studies performed on clinical 1.5 and 3 Tesla scanners. Healthy subjects and patients with nonischemic cardiomyopathy, dilated (DCM) or hypertrophic disease, New York Heart Association (NYHA) class I-IV heart failure (HF), or with anterior myocardial infarction are included. Three-layer neural-networks were created to classify disease and to differentiate DCM, hypertrophy and clinical NYHA class in HF patients using leave-one-out training. Network performance was assessed using 'confusion matrices' and 'area-under-the-curve' (AUC) analyses of 'receiver operating curves'. Possible methodological bias and network imbalance were tested by segregating 1.5 and 3 Tesla data, and by data augmentation by random interpolation of nearest neighbors, respectively. RESULTS: The network differentiated healthy, HF and non-HF cardiac disease with an overall accuracy of 84% and AUC > 90% for each category using the four CK metabolic parameters, alone. HF patients with DCM, hypertrophy, and different NYHA severity were differentiated with ~ 80% overall accuracy independent of CMRS methodology. CONCLUSIONS: While sample-size was limited in some sub-classes, a neural network classifier applied to noninvasive cardiac 31P CMRS data, could serve as a metabolic biomarker for common disease types and HF severity with clinically-relevant accuracy. Moreover, the network's ability to individually classify disease and HF severity using CK metabolism alone, implies an intimate relationship between CK metabolism and disease, with subtle underlying phenotypic differences that enable their differentiation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00181259.

SNR optimized 31 P functional MRS to detect mitochondrial and extracellular pH change during visual stimulation.

Energy metabolism of the human visual cortex was investigated by performing 31 P functional MRS. INTRODUCTION: The human brain is known to be the main glucose demanding organ of the human body and neuronal activity can increase this energy demand. In this study we investigate whether alterations in pH during activation of the brain can be observed with MRS, focusing on the mitochondrial inorganic phosphate (Pi) pool as potential marker of energy demand. METHODS: Six participants were scanned with 16 consecutive 31 P-MRSI scans, which were divided in 4 blocks of 8:36 minutes of either rest or visual stimulation. Since the signals from the mitochondrial compartments of Pi are low, multiple approaches to achieve high SNR 31 P measurements were combined. This included: a close fitting 31 P RF coil, a 7 T-field strength, Ernst angle acquisitions and a stimulus with a large visual angle allowing large spectroscopy volumes containing activated tissue. RESULTS: The targeted resonance downfield of the main Pi peak could be distinguished, indicating the high SNR of the 31 P spectra. The peak downfield of the main Pi peak is believed to be connected to mitochondrial performance. In addition, a BOLD effect in the PCr signal was observed as a signal increase of 2-3% during visual stimulation as compared to rest. When averaging data over multiple volunteers, a small subtle shift of about 0.1 ppm of the downfield Pi peak towards the main Pi peak could be observed in the first 4 minutes of visual stimulation, but no longer in the 4 to 8 minute scan window. Indications of a subtle shift during visual stimulation were found, but this effect remains small and should be further validated. CONCLUSION: Overall, the downfield peak of Pi could be observed, revealing opportunities and considerations to measure specific acidity (pH) effects in the human visual cortex.

Effects of Coenzyme Q10 on Skeletal Muscle Oxidative Metabolism in Statin Users Assessed Using 31P Magnetic Resonance Spectroscopy: a Randomized Controlled Study.

OBJECTIVES: Statins partially block the production of coenzyme Q10 (CoQ10), an essential component for mitochondrial function. Reduced skeletal muscle mitochondrial oxidative capacity has been proposed to be a cause of statin myalgia and can be measured using 31phosphorus magnetic resonance spectroscopy (31P-MRS). The purpose of this study is to assess the effect of CoQ10 oral supplementation on mitochondrial function in statin users using 31P-MRS. DESIGN/SETTING: In this randomized, double-blind, placebo-controlled pilot study, 21 adults aged 47-73 were randomized to statin+placebo (n=9) or statin+CoQ10 (n=12). Phosphocreatine (PCr) recovery kinetics of calf muscles were assessed at baseline (off statin and CoQ10) and 4 weeks after randomization to either statin+CoQ10 or statin+placebo. RESULTS: Baseline and post-treatment PCr recovery kinetics were assessed for 19 participants. After 4 weeks of statin+ CoQ10 or statin+placebo, the overall relative percentage change (100*(baseline-follow up)/baseline) in PCr recovery time was -15.1% compared with baseline among all participants, (p-value=0.258). Participants randomized to statin+placebo (n=9) had a relative percentage change in PCr recovery time of -18.9%, compared to -7.7% among participants (n=10) receiving statin+CoQ10 (p-value=0.448). CONCLUSIONS: In this pilot study, there was no significant change in mitochondrial function in patients receiving 4 weeks of statin+CoQ10 oral therapy when compared to patients on statin+placebo.

Extratemporal abnormalities in phosphorus magnetic resonance spectroscopy of patients with mesial temporal sclerosis / Anormalidades extratemporais na espectroscopia de fósforo por ressonância magnética em pacientes com esclerose mesial temporal

ABSTRACT Objective We evaluated extratemporal metabolic changes with phosphorus magnetic resonance spectroscopy (31P-MRS) in patients with unilateral mesial temporal sclerosis (MTS). Method 31P-MRS of 33 patients with unilateral MTS was compared with 31 controls. The voxels were selected in the anterior, posterior insula-basal ganglia (AIBG, PIBG) and frontal lobes (FL). Relative values of phosphodiesters- PDE, phosphomonoesters-PME, inorganic phosphate - Pi, phosphocreatine- PCr, total adenosine triphosphate [ATPt = γ- + a- + b-ATP] and the ratios PCr/ATPt, PCr/γ-ATP, PCr/Pi and PME/PDE were obtained. Results We found energetic abnormalities in the MTS patients compared to the controls with Pi reduction bilaterally in the AIBG and ipsilaterally in the PIBG and the contralateral FL; there was also decreased PCr/γ-ATP in the ipsilateral AIBG and PIBG. Increased ATPT in the contralateral AIBG and increased γ-ATP in the ipsilateral PIBG were detected. Conclusion Widespread energy dysfunction was detected in patients with unilateral MTS.

RESUMO Objetivo Nós avaliamos as alterações metabóblicas através da espectroscopia de fósforo por ressonância magnética (31P-MRS) em pacientes com esclerose mesial temporal (EMT) unilateral. Método 31P-MRS de 33 pacientes com EMT unilateral foram comparadas aos de 31 controles. Foram selecionados os voxels nas regiões insulonuclear anterior e posterior (RINA e RINP) e frontal (RF). Os valores relativos de fosfodiésteres – PDE, fosfomonoésteres- PME, fosfato inorgânico- Pi, fosfocreatina –PCr, adenosina trifosfato total [ATPt = γ- + a- + b-ATP] e as razões PCr/ATPt, PCr/γ-ATP, PCr/Pi e PME/PDE foram obtidas. Resultados Nós encontramos anormalidades em pacientes com EMT em comparação aos controles. Redução de Pi nas RINA bilateralmente, RINP ipsilateral e RF contralateral, redução de PCr/γ-ATP nas RINA e RINP ipsilaterais foram detectadas. Aumentos de ATPT na RINA contralateral e aumento de γ-ATP na RINP ipsilateral também foram encontradas. Conclusão Disfunção energética difusa foi encontrada em pacientes com EMT unilateral.

Brain energy metabolism in early MSA-P: A phosphorus and proton magnetic resonance spectroscopy study.

INTRODUCTION: Recently, mutations in the COQ2 gene, encoding for an enzyme involved in coenzyme Q10 biosynthesis, have been suggested to confer susceptibility risk for multiple system atrophy (MSA). Thus, the possible role of mitochondrial dysfunction in the pathophysiology of MSA has emerged. Here, we studied brain energy metabolism in vivo in early MSA-parkinsonism (MSA-P) patients and compared to healthy controls. METHODS: We have used combined phosphorus and proton magnetic resonance spectroscopy to measure high- and low-energy phosphates in the basal ganglia of early (Hoehn and Yahr stage I-III), probable MSA-P patients (N = 9) compared to healthy controls (N = 9). RESULTS: No significant changes in the high energy phosphates and other parameters reflecting the energy status of the cells were found in the basal ganglia of MSA-P patients compared to healthy controls. N-acetylaspartate was significantly reduced in MSA-P compared to healthy controls and correlated with the Unified Multiple System Atrophy Rating Scale. CONCLUSION: Brain energy metabolism in early MSA-P is not impaired, despite the presence of impaired neuronal integrity. This may imply that mitochondrial dysfunction may not play a primary role in the pathophysiology of MSA, at least in European populations.

Widespread pH abnormalities in patients with malformations of cortical development and epilepsy: a phosphorus-31 brain MR spectroscopy study.

INTRODUCTION: Neuroimaging studies demonstrate that not only the lesions of malformations of cortical development (MCD) but also the normal-appearing parenchyma (NAP) present metabolic impairments, as revealed with (1)H-MRS. We have previously detected biochemical disturbances in MCD lesions with phosphorus-31 magnetic resonance spectroscopy (31P-MRS). Our hypothesis is that pH abnormalities extend beyond the visible lesions. METHODS: Three-dimensional 31P-MRS at 3.0 T was performed in 37 patients with epilepsy and MCD, and in 31 matched-control subjects. The patients were assigned into three main MCD subgroups: cortical dysplasia (n=10); heterotopia (n=14); schizencephaly/polymicrogyria (n=13). Voxels (12.5 cm3) were selected in five homologous regions containing NAP: right putamen; left putamen; frontoparietal parasagittal cortex; right centrum semiovale; and left centrum semiovale. Robust methods of quantification were applied, and the intracellular pH was calculated with the chemical shifts of inorganic phosphate (Pi) relative to phosphocreatine (PCr). RESULTS: In comparison to controls and considering a Bonferroni adjusted p-value <0.01, MCD patients presented significant reduction in intracellular pH in the frontoparietal parasagittal cortex (6.985±0.022), right centrum semiovale (7.004±0.029), and left centrum semiovale (6.995±0.030), compared to controls (mean values±standard deviations of 7.087±0.048, 7.096±0.042, 7.088±0.045, respectively). Dunnet and Dunn tests demonstrated that the differences in pH values remained statistically significant in all MCD subgroups. No significant differences were found for the putamina. CONCLUSION: The present study demonstrates widespread acidosis in the NAP, and reinforces the idea that MCD visible lesions are only the tip of the iceberg.

Brown adipose tissue dynamics in wild-type and UCP1-knockout mice: in vivo insights with magnetic resonance.

We used noninvasive magnetic resonance imaging (MRI) and magnetic resonance spectroscopy to compare interscapular brown adipose tissue (iBAT) of wild-type (WT) and uncoupling protein 1 (UCP1)-knockout mice lacking UCP1-mediated nonshivering thermogenesis (NST). Mice were sequentially acclimated to an ambient temperature of 30°C, 18°C, and 5°C. We detected a remodeling of iBAT and a decrease in its lipid content in all mice during cold exposure. Ratios of energy-rich phosphates (ATP/ADP, phosphocreatine/ATP) in iBAT were maintained stable during noradrenergic stimulation of thermogenesis in cold- and warm-adapted mice and no difference between the genotypes was observed. As free fatty acids (FFAs) serve as fuel for thermogenesis and activate UCP1 for uncoupling of oxidative phosphorylation, brown adipose tissue is considered to be a main acceptor and consumer of FFAs. We measured a major loss of FFAs from iBAT during noradrenergic stimulation of thermogenesis. This mobilization of FFAs was observed in iBAT of WT mice as well as in mice lacking UCP1. The high turnover and the release of FFAs from iBAT suggests an enhancement of lipid metabolism, which in itself contributes to the sympathetically activated NST and which is independent from uncoupled respiration mediated by UCP1. Our study demonstrates that MRI, besides its potential for visualizing and quantification of fat tissue, is a valuable tool for monitoring functional in vivo processes like lipid and phosphate metabolism during NST.

Energy status and metabolism in intracranial space occupying lesions: a prospective 31p spectroscopic study.

AIM: Intracranial space occupying lesions can be infective or tumour. There are various advanced Magnetic resonance imaging techniques like perfusion, diffusion and proton spectroscopy which can differentiate between them. However, (31) Phosphorus spectroscopy studies the energy status and the metabolism pattern of various tissues and can be used potentially to differentiate between them depending on their Metabolism pattern. Thus, we aimed to study energy status of various intracranial lesions and try to differentiate between them including grades of gliomas. MATERIALS AND METHODS: (31)PMRS was done in 1.5T MRI in 43 patients prior to surgery or through/via stereo-tactic biopsy, of which 25 were men and 18 women with mean age 41.34 y ranging from 7-71 y. Single voxel phosphorus spectroscopy was done from the solid portion of the lesions and data was analysed and post processed. RESULTS: Study includes Lymphoma (n=6), Grade 1 and 2 glioma (n=5), grade 3 glioma (n=9), grade 4 glioma(n=6), metastases (n=5), tuberculoma (n=7) and pyogenic abscesses (n=5). The integral values of PME, Pi, PDE, γ-ATP, α-ATP, ß-ATP with reference to the position of PCr were calculated along with various ratios. Integral values of Pi and PDE were significantly increased in metastases but decreased in gliomas grade 1-2 compared to other pathologic conditions. Mean integral values of LEP (low energy phosphates) and total phosphates were significantly decreased in gliomas grades 1 and 2 and increased in metastases when compared with other pathologic conditions. PCr /Pi was increased in glioma grades 1, 2 and 3 but decreased in metastases; the significance was observed only in gliomas grade 3 and metastases. Metabolic ratios of PDE/ß ATP and Pi/ßATP were decreased in glioma grades 1 and 2 and increased in metastases with statistical significance. CONCLUSION: (31)PMRS may help in differentiating primary from secondary lesions and assess grades of gliomas.

Phosphorus metabolites in human skin and muscle obtained by phosphorus-31 magnetic resonance spectroscopy.

BACKGROUND/AIMS: Characterization of skin phosphometabol-ism in vivo by non-invasive magnetic resonance spectroscopy (MRS) might allow assessment of ischemic or irradiative damage. METHODS: Based on a study of 17 healthy volunteers, we present statistical analyses for intra- and inter-tissue metabolite concentration ratios, as well as for pH and [Mg(2+) ]. RESULTS: Results contrasted steady-state energy metabolism in skin and muscle, showing lower phosphocreatine/ATP, higher percentage of inorganic phosphate, phosphodiesters and phos-phomonoesters, and higher pH and [Mg(2+) ] in skin than in muscle. CONCLUSION: Results were consistent with known skin physiology and structure and suggested an inverse relationship between skin phosphodiester levels and melanin.