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1.
Do nuclear magnetic resonance (NMR)-based metabolomics improve the prediction of pregnancy-related disorders? Findings from a UK birth cohort with independent validation.
McBride, N, Yousefi, P, White, SL, Poston, L, Farrar, D, Sattar, N, Nelson, SM, Wright, J, Mason, D, Suderman, M, et al
BMC medicine. 2020;(1):366
Abstract
BACKGROUND Prediction of pregnancy-related disorders is usually done based on established and easily measured risk factors. Recent advances in metabolomics may provide earlier and more accurate prediction of women at risk of pregnancy-related disorders. METHODS We used data collected from women in the Born in Bradford (BiB; n = 8212) and UK Pregnancies Better Eating and Activity Trial (UPBEAT; n = 859) studies to create and validate prediction models for pregnancy-related disorders. These were gestational diabetes mellitus (GDM), hypertensive disorders of pregnancy (HDP), small for gestational age (SGA), large for gestational age (LGA) and preterm birth (PTB). We used ten-fold cross-validation and penalised regression to create prediction models. We compared the predictive performance of (1) risk factors (maternal age, pregnancy smoking, body mass index (BMI), ethnicity and parity) to (2) nuclear magnetic resonance-derived metabolites (N = 156 quantified metabolites, collected at 24-28 weeks gestation) and (3) combined risk factors and metabolites. The multi-ethnic BiB cohort was used for training and testing the models, with independent validation conducted in UPBEAT, a multi-ethnic study of obese pregnant women. RESULTS Maternal age, pregnancy smoking, BMI, ethnicity and parity were retained in the combined risk factor and metabolite models for all outcomes apart from PTB, which did not include maternal age. In addition, 147, 33, 96, 51 and 14 of the 156 metabolite traits were retained in the combined risk factor and metabolite model for GDM, HDP, SGA, LGA and PTB, respectively. These include cholesterol and triglycerides in very low-density lipoproteins (VLDL) in the models predicting GDM, HDP, SGA and LGA, and monounsaturated fatty acids (MUFA), ratios of MUFA to omega 3 fatty acids and total fatty acids, and a ratio of apolipoprotein B to apolipoprotein A-1 (APOA:APOB1) were retained predictors for GDM and LGA. In BiB, discrimination for GDM, HDP, LGA and SGA was improved in the combined risk factors and metabolites models. Risk factor area under the curve (AUC 95% confidence interval (CI)): GDM (0.69 (0.64, 0.73)), HDP (0.74 (0.70, 0.78)) and LGA (0.71 (0.66, 0.75)), and SGA (0.59 (0.56, 0.63)). Combined risk factor and metabolite models AUC 95% (CI): GDM (0.78 (0.74, 0.81)), HDP (0.76 (0.73, 0.79)) and LGA (0.75 (0.70, 0.79)), and SGA (0.66 (0.63, 0.70)). For GDM, HDP and LGA, but not SGA, calibration was good for a combined risk factor and metabolite model. Prediction of PTB was poor for all models. Independent validation in UPBEAT at 24-28 weeks and 15-18 weeks gestation confirmed similar patterns of results, but AUCs were attenuated. CONCLUSIONS Our results suggest a combined risk factor and metabolite model improves prediction of GDM, HDP and LGA, and SGA, when compared to risk factors alone. They also highlight the difficulty of predicting PTB, with all models performing poorly.
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2.
Safety and effectiveness of therapeutic magnetic resonance in diabetic foot ulcers: a prospective randomised controlled trial.
Piaggesi, A, Sambataro, M, Nicoletti, C, Goretti, C, Lacopi, E, Coppelli, A
Journal of wound care. 2016;(12):704-711
Abstract
OBJECTIVE To test the efficacy and safety of therapeutic magnetic resonance (TMR) in the management of diabetic foot ulcers (DFU), the authors designed a prospective randomised controlled trial in three highly specialised diabetic foot clinics. METHOD All the patients consecutively visited in a period of 18 months were screened according to the inclusion (presence of an ulcer >1 cm2 in the foot lasting at least 6 weeks; ABPI>0.6; consent to participate in the study) and exclusion (Charcot's foot; local or systemic infections; chronic renal failure; any wearable electrically-driven life-supporting device) criteria. Patients, who were treated according to international guideline protocols, were randomised into two groups: group A received for four weeks the sham application of TMR, while group B received the active TMR for the same period. People were followed-up to 10 weeks and healing rate (HR), healing time (HT), rate of granulation tissue on wound bed (% GT), reduction of the area of the lesion (∆AL) and a score (0-3) evaluating erythema, oedema, pain and tenderness, respectively, were measured. Adverse events (AE) were registered and monitored throughout the study. RESULTS No differences were observed in HR, HT and ∆AL between the two groups during follow-up, while % GT and the scores for erythema, oedema and pain at 10 weeks showed significant (p<0.05) improvements in group B compared with group A and versus baseline. When restricted to non-ischaemic patients (ABPI>0.8), ∆AL was significantly (p<0.05) more pronounced in group B than in group A. No difference in AE occurrence was observed between the two groups. CONCLUSION Our study, despite not being able to demonstrate the effectiveness of TMR on healing rate at 10 weeks, with 4 weeks of active treatment in neuro-ischaemic DFUs, shows positive effects on clinical aspects of the DFU and is associated with a significant increase of GT in the wound bed. DECLARATION OF INTEREST The study has been fully sponsored by Thereson S.p.A., manufacturer of TMR devices.
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3.
Evaluation of the lactate-to-N-acetyl-aspartate ratio defined with magnetic resonance spectroscopic imaging before radiation therapy as a new predictive marker of the site of relapse in patients with glioblastoma multiforme.
Deviers, A, Ken, S, Filleron, T, Rowland, B, Laruelo, A, Catalaa, I, Lubrano, V, Celsis, P, Berry, I, Mogicato, G, et al
International journal of radiation oncology, biology, physics. 2014;(2):385-93
Abstract
PURPOSE Because lactate accumulation is considered a surrogate for hypoxia and tumor radiation resistance, we studied the spatial distribution of the lactate-to-N-acetyl-aspartate ratio (LNR) before radiation therapy (RT) with 3D proton magnetic resonance spectroscopic imaging (3D-(1)H-MRSI) and assessed its impact on local tumor control in glioblastoma (GBM). METHODS AND MATERIALS Fourteen patients with newly diagnosed GBM included in a phase 2 chemoradiation therapy trial constituted our database. Magnetic resonance imaging (MRI) and MRSI data before RT were evaluated and correlated to MRI data at relapse. The optimal threshold for tumor-associated LNR was determined with receiver-operating-characteristic (ROC) curve analysis of the pre-RT LNR values and MRI characteristics of the tumor. This threshold was used to segment pre-RT normalized LNR maps. Two spatial analyses were performed: (1) a pre-RT volumetric comparison of abnormal LNR areas with regions of MRI-defined lesions and a choline (Cho)-to- N-acetyl-aspartate (NAA) ratio ≥ 2 (CNR2); and (2) a voxel-by-voxel spatial analysis of 4,186,185 voxels with the intention of evaluating whether pre-RT abnormal LNR areas were predictive of the site of local recurrence. RESULTS A LNR of ≥ 0.4 (LNR-0.4) discriminated between tumor-associated and normal LNR values with 88.8% sensitivity and 97.6% specificity. LNR-0.4 voxels were spatially different from those of MRI-defined lesions, representing 44% of contrast enhancement, 64% of central necrosis, and 26% of fluid-attenuated inversion recovery (FLAIR) abnormality volumes before RT. They extended beyond the overlap with CNR2 for most patients (median: 20 cm(3); range: 6-49 cm(3)). LNR-0.4 voxels were significantly predictive of local recurrence, regarded as contrast enhancement at relapse: 71% of voxels with a LNR-0.4 before RT were contrast enhanced at relapse versus 10% of voxels with a normal LNR (P<.01). CONCLUSIONS Pre-RT LNR-0.4 in GBM indicates tumor areas that are likely to relapse. Further investigations are needed to confirm lactate imaging as a tool to define additional biological target volumes for dose painting.
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4.
Reproducibility of 3D 1H MR spectroscopic imaging of the prostate at 1.5T.
Lagemaat, MW, Zechmann, CM, Fütterer, JJ, Weiland, E, Lu, J, Villeirs, GM, Holshouser, BA, van Hecke, P, Lemort, M, Schlemmer, HP, et al
Journal of magnetic resonance imaging : JMRI. 2012;(1):166-73
Abstract
PURPOSE To determine the reproducibility of 3D proton magnetic resonance spectroscopic imaging ((1)H-MRSI) of the human prostate in a multicenter setting at 1.5T. MATERIALS AND METHODS Fourteen subjects were measured twice with 3D point-resolved spectroscopy (PRESS) (1)H-MRSI using an endorectal coil. MRSI voxels were selected in the peripheral zone and combined central gland at the same location in the prostate in both measurements. Voxels with approved spectral quality were included to calculate Bland-Altman parameters for reproducibility from the choline plus creatine to citrate ratio (CC/C). The repeated spectroscopic data were also evaluated with a standardized clinical scoring system. RESULTS A total of 74 voxels were included for reproducibility analysis. The complete range of biologically interesting CC/C ratios was covered. The overall within-voxel standard deviation (SD) of the CC/C ratio of the repeated measurements was 0.13. This value is equal to the between-subject SD of noncancer prostate tissue. In >90% of the voxels the standardized clinical score did not differ relevantly between the measurements. CONCLUSION Repeated measurements of in vivo 3D (1)H-MRSI of the complete prostate at 1.5T produce equal and quantitative results. The reproducibility of the technique is high enough to provide it as a reliable tool in assessing tumor presence in the prostate.
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5.
Assessment of citrullinated myelin by 1H-MR spectroscopy in early-onset multiple sclerosis.
Oguz, KK, Kurne, A, Aksu, AO, Karabulut, E, Serdaroglu, A, Teber, S, Haspolat, S, Senbil, N, Kurul, S, Anlar, B
AJNR. American journal of neuroradiology. 2009;(4):716-21
Abstract
BACKGROUND AND PURPOSE Myelin instability and citrullinated myelin basic protein have been demonstrated in the brains of patients with chronic and fulminating forms of multiple sclerosis (MS). Our aim was to trace citrulline in the brains of patients with early-onset MS by using proton MR spectroscopy ((1)H-MR spectroscopy). MATERIALS AND METHODS A short-echo single-voxel (1)H-MR spectroscopy by using the point-resolved proton spectroscopy sequence was performed in 27 patients with MS and 23 healthy subjects. Voxels of interest were chronic demyelinating lesions (CDLs, n = 25) and normal-appearing white matter (NAWM, n = 25) on T2-weighted imaging, and when available in patients with MS, enhancing demyelinating lesions (EDLs, n = 8). Frontal white matter (WM) was studied in control subjects. N-acetylaspartate, choline, and myo-inositol (mIns)-creatine (Cr) ratios and the presence of a citrulline peak were noted. RESULTS Citrulline peaks were more frequently observed in patients with MS than in control subjects (P = .035), located in the NAWM in 8/25 (32%), in CDLs in 7/25 (28%), and in EDLs of 1/8 (12.5%) patients with MS. The presence of citrulline and measured metabolite/Cr ratios was not related to age at imaging, age at disease onset, duration of disease, or number of relapses. There was no significant metabolic difference between the NAWM of patients with MS and the WM of the control subjects. mIns/Cr was significantly greater in CDLs compared with the NAWM of patients with MS and the WM of healthy subjects. CONCLUSIONS Citrulline was more frequently identified in the brains of patients with early-onset MS than in healthy subjects by (1)H-MR spectroscopy, suggesting an association of increased citrullination of myelin proteins with demyelinating diseases.
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6.
Longitudinal magnetic resonance spectroscopic imaging of primary progressive multiple sclerosis patients treated with glatiramer acetate: multicenter study.
Sajja, BR, Narayana, PA, Wolinsky, JS, Ahn, CW, ,
Multiple sclerosis (Houndmills, Basingstoke, England). 2008;(1):73-80
Abstract
Multicenter proton magnetic resonance spectroscopic imaging (MRSI) studies were performed on 58 primary progressive multiple sclerosis (PPMS) patients from four centers for investigating the efficacy of glatiramer acetate (GA) treatment. These patients were drawn from 943 subjects who participated in the PROMiSe trial. In these MRSI studies, patients were followed over a period of 3 years. MRSI data were acquired by all the centers using the same pulse sequence, and spectral analysis was performed at a single site using a customized analysis software package. Quantitative metabolite ratios, N-acetyl aspartate (NAA)/creatine (Cr) and choline (Cho)/Cr, were compared between GA-treated and placebo-treated PPMS patients. There was no significant difference in metabolite ratios between GA-treated and placebo-treated patients. The difference in metabolite ratios between the normal-appearing tissues (NAT) and lesion-containing regions (LCR) in GA treated patients was not significantly different from placebo treated patients. Strong lipid resonances, even in the absence of lesions, were observed on MRSI data in both gray matter and white matter in placebo- and GA-treated PPMS patients. No significant difference in number of patients with lipids between the two groups over a period of 3 years was found.
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7.
Muscle-associated triglyceride measured by computed tomography and magnetic resonance spectroscopy.
Larson-Meyer, DE, Smith, SR, Heilbronn, LK, Kelley, DE, Ravussin, E, Newcomer, BR, ,
Obesity (Silver Spring, Md.). 2006;(1):73-87
Abstract
OBJECTIVE Muscle triglyceride can be assessed in vivo using computed tomography (CT) and 1H magnetic resonance spectroscopy (MRS), two techniques that are based on entirely different biophysical principles. Little is known, however, about the cross-correlation between these techniques and their test-retest reliability. RESEARCH METHODS AND PROCEDURES We compared mean muscle attenuation (MA) in soleus and tibialis anterior (TA) muscles measured by CT with intra- and extramyocellular lipids (IMCL and EMCL, respectively) measured by MRS in 51 volunteers (26 to 72 years of age, BMI = 25.5 to 39.3 kg/m2). MA of midthighs was also measured in a subset (n = 19). Test-retest measurements were performed by CT (n = 6) and MRS (n = 10) in separate sets of volunteers. RESULTS MA of soleus was significantly associated with IMCL (r = -0.64) and EMCL, which by multiple regression analysis was explained mostly by IMCL (p < 0.001) rather than EMCL (beta = -0.010, p = 0.94). Muscle triglyceride was lower in TA than in soleus, and MA of TA was significantly correlated with EMCL (r = -0.40) but not IMCL (r = -0.16). By CT, MA of midthighs was correlated with MA in soleus (r = 0.40, p = 0.07) and whole calf (r = 0.62, p < 0.05). Finally, both MA and IMCL were highly reliable in soleus (coefficient of variation = < 2% and 6.7%, respectively) and less reliable in TA (4% and 10%, respectively). DISCUSSION These results support the use of both CT and MRS as reliable methods for assessing skeletal muscle lipid.
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8.
In vivo 31P MR spectral patterns and reproducibility in cancer patients studied in a multi-institutional trial.
Arias-Mendoza, F, Payne, GS, Zakian, KL, Schwarz, AJ, Stubbs, M, Stoyanova, R, Ballon, D, Howe, FA, Koutcher, JA, Leach, MO, et al
NMR in biomedicine. 2006;(4):504-12
Abstract
The standardization and reproducibility of techniques required to acquire anatomically localized 31P MR spectra non-invasively while studying tumors in cancer patients in a multi-institutional group at 1.5 T are reported. This initial group of patients was studied from 1995 to 2000 to test the feasibility of acquiring in vivo localized 31P MRS in clinical MR spectrometers. The cancers tested were non-Hodgkin's lymphomas, sarcomas of soft tissue and bone, breast carcinomas and head and neck carcinomas. The best accrual and spectral quality were achieved with the non-Hodgkin's lymphomas. The initial analysis of the spectral values of the sum of phosphoethanolamine plus phosphocholine normalized by the content of nucleotide triphosphates in a homogeneous sample of 32 NHL patients studied by in vivo (31)P MRS showed good reproducibility among different institutions. No statistical differences were found between the institution with the largest number of cases accrued and the rest of the multi-institutional NHL data (2.28 +/- 0.64, mean +/- standard error; n = 17, vs 2.08 +/- 0.14, n = 15). The preliminary data reported demonstrate that the institutions involved in this trial are obtaining reproducible 31P MR spectroscopic data non-invasively from human tumors. This is a fundamental prerequisite for the international cooperative group to be able to demonstrate the clinical value of the normalized determination of phosphoethanolamine plus phosphocholine by 31P MRS as predictor for treatment response in cancer patients.
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9.
A multi-center 1H MRS study of the AIDS dementia complex: validation and preliminary analysis.
Lee, PL, Yiannoutsos, CT, Ernst, T, Chang, L, Marra, CM, Jarvik, JG, Richards, TL, Kwok, EW, Kolson, DL, Simpson, D, et al
Journal of magnetic resonance imaging : JMRI. 2003;(6):625-33
Abstract
PURPOSE To demonstrate the technical feasibility and reliability of a multi-center study characterizing regional levels of the brain metabolite ratios choline (Cho)/creatine (Cr) and myoinositol (MI)/Cr, markers of glial cell activity, and N-acetyl aspartate (NAA)/Cr, a marker of mature neurons, in subjects with AIDS dementia complex (ADC). MATERIALS AND METHODS Using an automated protocol (GE PROBE-P), short echo time spectra (TE = 35 msec) were obtained at eight sites from uniformly prepared phantoms and from three brain regions (frontal white matter, basal ganglia, and parietal cortex) of normal volunteers and ADC and HIV-negative subjects. RESULTS A random-effects model of the phantom and volunteer data showed no significant inter-site differences. Feasibility of a multi-center study was further validated by detection of significant differences between the metabolite ratios of ADC subjects and HIV-negative controls. ADC subjects exhibited significantly higher Cho/Cr and MI/Cr in the basal ganglia and significantly reduced NAA/Cr and significantly higher MI/Cr in the frontal white matter. These results are consistent with the predominantly subcortical distribution of the pathologic abnormalities associated with ADC. CONCLUSION This is the first study to ascertain and validate the reliability and reproducibility of a short echo time (1)H-MRS acquisition sequence from multiple brain regions in a multi-center setting. It should now be possible to examine the regional effects of HIV infection in the brain in a large number of subjects and to study the metabolic effects of new therapies for the treatment of ADC in a clinical trial setting.