Proton magnetic resonance spectroscopy of the central,transition and peripheral zones of the prostate: assignments and correlation with histopathology

Proton magnetic resonance spectroscopy (MRS) is used to compare the chemistry of the transition, central and peripheral zones of the prostate. The assignments are made using two-dimensional correlated spectroscopy and the results compared with histopathology. The chemistry associated with benign prostatic hyperplasia (BPH), prostate intraepithelial neoplasia (PIN) and malignant biopsy tissues are described. There are distinct MR spectral patterns for glandular and stromal BPH, PIN and adenocarcinoma. Importantly, there are also different spectral patterns from BPH in the transitional and central zones when compared to BPH in the peripheral zone. A pattern recognition method is used to analyze the MR spectra from the biopsy specimens. The resultant mathematical classifiers generated a high level of accuracy (sensitivity and specificity of 100 and 97%). It was found that for this accuracy to be achieved, the classifiers need to be developed by comparing the spectra with specialist serial sectioned histopathology. With serial sectioned pathology the pattern recognition method was capable of identifying less than 5% of adenocarcinoma in a given piece of tissue. Many of the chemicals identified in the biopsy specimens are available for inspection from the prostate, in vivo, at 3 T.     

Two-dimensional MR spectroscopy of healthy and cancerous prostates in vivo

Objectives  A major goal of this article is to summarize the current status of evaluating prostate metabolites non-invasively using spatially resolved two-dimensional (2D) MR Spectroscopy (MRS). Materials and Methods  Due to various technical challenges, the spatially resolved versions of 2D MRS techniques are currently going through the developmental stage. During the last decade, four different versions of 2D MRS sequences have been successfully implemented on 3T and 1.5T MRI scanners manufactured by three different vendors. These sequences include half and maximum echo sampled J-resolved spectroscopy (JPRESS), S-PRESS and L-COSY, which are single volume localizing sequences, and the multi-voxel based JPRESS sequence. Results  Even though greater than 1ml voxels have been used, preliminary evaluations of 2D JPRESS, S-PRESS and L-COSY sequences have demonstrated unambiguous detection of citrate, creatine, choline, spermine and more metabolites in human prostates. ProFIT-based quantitation of JPRESS and L-COSY data clearly shows the superiority of 2D MRS over conventional one-dimensional (1D) MRS and more than six metabolites have been successfully quantified. These sequences have been evaluated in a small group of prostate pathologies and pilot investigations using these sequences show promising results in prostate pathologies. Conclusion  Implementation of the state-of-the-art 2D MRS techniques and preliminary evaluation in prostate pathologies are discussed in this review. Even though these techniques are going through developmental and early testing phases, it is evident that 2D MRS can be easily added on to any clinical Magnetic Resonance Imaging (MRI) protocol to non-invasively record the biochemical contents of the prostate.     

<Superscript>1</Superscript>H MR spectroscopy as a diagnostic tool for cerebral creatine deficiency

Objective  Total creatine (tCr) constitutes one of the most prominent signals in human brain MR spectra. A significant decrease in the tCr signal indicates a severe disorder of creatine metabolism. We describe the potential of ¹H MR spectroscopy in differential diagnosis of creatine transporter (SLC6A8) deficiency syndrome. Materials and methods  Two siblings, a 7-year-old female presenting with mild psychomotor delay, and a 5-year-old male with severe psychomotor retardation, epilepsy and autistic spectrum of problems including speech delay, underwent MR examination because of suspected creatine deficiency. After the MRI examination, ¹H MR spectroscopy using the CSI technique was performed. Results  Metabolic images of N-acetylaspartate, tCr and choline concentrations showed a very low tCr signal in the male, which was approximately three times lower than in his sister (male/female/controls: tCr = 1.6/4.6/7.5 mM). Despite creatine supplementation, no improvement in clinical status and tCr concentration in the MR spectra of the male was observed and diagnosis of SLC6A8 deficiency was proposed. Sequence analysis of the SLC6A8 gene revealed a novel pathogenic frameshift mutation c.219delC; p.Asn74ThrfsX23, hemizygous in the male and heterozygous in the female. Conclusions  The diagnosis of X-linked mental retardation caused by the SLC6A8 deficiency can be independently established by ¹H MR spectroscopy.     

Monitoring and correcting spatio-temporal variations of the MR scanner’s static magnetic field

The homogeneity and stability of the static magnetic field are of paramount importance to the accuracy of MR procedures that are sensitive to phase errors and magnetic field inhomogeneity. It is shown that intense gradient utilization in clinical horizontal-bore superconducting MR scanners of three different vendors results in main magnetic fields that vary on a long time scale both spatially and temporally by amounts of order 0.8–2.5 ppm. The observed spatial changes have linear and quadratic variations that are strongest along the z direction. It is shown that the effect of such variations is of sufficient magnitude to completely obfuscate thermal phase shifts measured by proton-resonance frequency-shift MR thermometry and certainly affect accuracy. In addition, field variations cause signal loss and line-broadening in MR spectroscopy, as exemplified by a fourfold line-broadening of metabolites over the course of a 45 min human brain study. The field variations are consistent with resistive heating of the magnet structures. It is concluded that correction strategies are required to compensate for these spatial and temporal field drifts for phase-sensitive MR protocols. It is demonstrated that serial field mapping and phased difference imaging correction protocols can substantially compensate for the drift effects observed in the MR thermometry and spectroscopy experiments.     

FID modulus: a simple and efficient technique to phase and align MR spectra

Object

The post-processing of MR spectroscopic data requires several steps more or less easy to automate, including the phase correction and the chemical shift assignment. First, since the absolute phase is unknown, one of the difficulties the MR spectroscopist has to face is the determination of the correct phase correction. When only a few spectra have to be processed, this is usually performed manually. However, this correction needs to be automated as soon as a large number of spectra is involved, like in the case of phase coherent averaging or when the signals collected with phased array coils have to be combined. A second post-processing requirement is the frequency axis assignment. In standard mono-voxel MR spectroscopy, this can also be easily performed manually, by simply assigning a frequency value to a well-known resonance (e.g. the water or NAA resonance in the case of brain spectroscopy). However, when the correction of a frequency shift is required before averaging a large amount of spectra (due to B ₀ spatial inhomogeneities in chemical shift imaging, or resulting from motion for example), this post-processing definitely needs to be performed automatically.

Materials and methods

Zero-order phase and frequency shift of a MR spectrum are linked respectively to zero-order and first-order phase variations in the corresponding free induction decay (FID) signal. One of the simplest ways to remove the phase component of a signal is to calculate the modulus of this signal: this approach is the basis of the correction technique presented here.

Results

We show that selecting the modulus of the FID allows, under certain conditions that are detailed, to automatically phase correct and frequency align the spectra. This correction technique can be for example applied to the summation of signals acquired from combined phased array coils, to phase coherent averaging and to B ₀ shift correction.

Conclusion

We demonstrate that working on the modulus of the FID signal is a simple and efficient way to both phase correct and frequency align MR spectra automatically. This approach is particularly well suited to brain proton MR spectroscopy.     

In vivo1H MR spectra analysis by means of second derivative method

Short echo time (TE) in vivo PRESS¹H MR spectra (2 T. TE = 35 ms) of normal brain were fitted in the frequency domain using the second derivative method. In this approach, local maxima and hidden peaks are found as local minima of spectrum second derivative. The Lorentzian robust minimisation procedure (referred to as maximum likelihood or m-estimate fitting) using Levenburg -Marquardt non-linear fitting engine was applied. Spectral lines were approximated under the assumption of the mixed Lorentzian/Gaussian lineshapes. The same procedure was applied to 18 proton spectra. The number of peaks found within the range of 0.74/4.2 parts per million (ppm) was 52 ± 3 and their positions were almost the same. The fitted lines were assigned on the basis of the J-pattern recalculated for the field strength of 2 T and by comparing the chemical shifts with the shifts in the single compound spectra. The ratios of main metabolites, such as NAA/Cr, Cho/Cr, Cho/NAA and ml/Cr, are in accord with those obtained earlier using the software supplied with the MR imager and the absolute concentrations ofN-acetylaspartate (NAA). choline containing compounds (Cho),myo Inositol (ml), glucose (Gle) and glutamate (Glu) obtained from the fit agree with those reported in literature, which confirms the usefulness of the second derivative method in routine analyses of¹H MR brain spectra.     

Role of magnetic resonance methods in the evaluation of prostate cancer: an Indian perspective

The challenges in detection, localization, and staging of prostate cancer have prompted the investigation of the role of various magnetic resonance (MR) methodologies in a large cohort of men prior to biopsy. The identification of suspicious areas of malignancy was carried out using magnetic resonance imaging (MRI), magnetic resonance spectroscopic imaging (MRSI) and diffusion-weighted imaging (DWI). Our data shows that apparent diffusion coefficient (ADC) may be a reliable marker to differentiate normal, benign, and malignant prostate tissues similar to the metabolite ratio. Also, the combined use of MRSI and DWI improves the diagnosis of prostate cancer. In this review, we present our experience on the use of MRI, MRSI and DWI methods in the assessment of prostate cancer in Indian men. Further, analysis of the comparison of the ADC and the metabolite ratio values reported in the literature across various patient populations are presented. An erratum to this article can be found at     

1H NMR-based metabolomic identification of at-risk areas after myocardial infarction in swine

Object ¹H NMR-based metabolic profiling has been used to investigate areas of the heart after an acute myocardial infarction. Methods Tissue was obtained from control, at-risk (areas that survive within the infarct zone) and necrotic myocardium after 48 min of left anterior descending coronary artery occlusion and 2 h of reperfusion in a swine model. HR-MAS (high resolution magic angle spectroscopy) spectra from intact tissue and tissue extract spectra were obtained for each region and statistical models were built for each type of spectra allowing differentiation between control, at-risk and necrotic heart. Results At-risk and, especially, necrotic areas have a reduced concentration of NMR visible metabolites as compared to control tissue, total creatine (phosphorilated and unphosphorilated) being the single most important metabolite in the different discriminant models. Creatine concentration decreased from 18.28 ± 0.84 μmols/g fresh weight in controls to 12.58 ± 2.89 (P < 0.05) and 9.96 ± 2.21 (P < 0.01) in at-risk and necrotic areas, respectively. Taurine and myo-inositol were also involved in the discriminant models. HR-MAS spectra also showed an increase in lipid signals at 0.9 and 1.28 ppm as markers of necrotic tissue. These results support the view that the analysis of in vivo ¹H MRS may have value in differentiating normal, at-risk and infarcted myocardium. This work was supported by Red de Enfermedades Cardiovasculares (RECAVA) CICYT SAF2005-01758 and EU Grant FP6-513595.     

Proton chemical shift imaging,metabolic maps,and single voxel spectroscopy of glial brain tumors

Seventeen patients with presumed glial brain tumors were examined with proton chemical shift imaging and single voxel spectroscopy that used different echo times. Metabolite resonances were evaluated by metabolic ratios and absolutely by correcting for coil load and comparison to phantom measurements. Metabolic images were created to visualize the metabolic changes. All patients showed spectra that were different from those measured in healthy control subjects. Spectral changes were also present in normal-appearing matter (NAM) that was distant from lesions. The resonance at 3.55 ppm which is usually assigned to bothmyo-inositol and glycine, was the only one to allow a discrimination between healthy volunteers, astrocytoma grade II, and glioblastoma multiforme (GBM) (p<0.02). From the different echo times used we conclude that an increase inhis resonance has to be assigned to glycine rather thanmyo-inositol. This resonance might be used to grade human gliomas more reliably. Total creatine (Cr) decreased more drastically with malignancy than N-acetylated metabolites (NA). This led to a higher NA/Cr ratio in GBM compared to astrocytoma grade II. NA/Cr was thus pseudonormal in GBM due to a change in both nominator and denominator. This study reveals the importance of comparing magnetic resonance spectroscopy data of lesions to spectra measured in identical localizations in healthy control subjects instead of NAM and the importance of quantifying single metabolic peaks instead of creating metabolic ratios in clinical magnetic resonance spectroscopy.     

Cervical cancer tissue characterized by high-resolution magic angle spinning MR spectroscopy

Objective: In recent years, high-resolution magic angle spinning (HR MAS) has provided the opportunity to explore detailed biochemical composition of intact tissue. Previous studies of intact cervical biopsies with high-resolution magnetic resonance spectroscopy (MRS) have correlated well with histopathology. Lactate level in cervical cancer tissue has been found to correlate to metastatic spread. The purpose of this study was to explore the potential of the HR MAS technique as a tool for chemical characterization of cervical cancer tissue. Materials and methods: Tissue samples from the cervix were collected after hysterectomy from patients with cervical cancer (n=8) and patients with nonmalignant disease (n=8). The tissue specimens were analyzed using HR MAS MR spectroscopy combined with principal component analysis (PCA). Results: The resulting spectra showed resolution comparable with high-resolution MR spectra of extracts. Multivariate analysis confirmed that MAS spectra classified according to patient diagnosis. Conclusion: Malignant tissue of the cervix differed from nonmalignant tissue with regard to higher levels of cholines and amino acid residues and lower levels of glucose.     

1H MR spectroscopic imaging with short and long echo time to discriminate glycine in glial tumours

OBJECT: To investigate glycine (Gly) concentrations in low- and high-grade gliomas based on (1)H MR spectroscopic imaging (MRSI) with short and long echo time (TE). Myoinositol (MI) and Gly appear at the same resonance frequency of 3.56 ppm, but due to strong coupling the MI signal dephases more rapidly. Therefore, their contribution to the 3.56 ppm signal should be distinguishable comparing MRSI data acquired at short and long TE. MATERIALS AND METHODS: (1)H MRSI (TE = 30 and 144 ms) was performed at 3 T in 29 patients with histopathological confirmed World Health Organization (WHO) grade II-IV gliomas and in FIVE healthy subjects. All spectra from the gliomas revealed increase of the 3.56 ppm resonance in the short TE spectra. Signal intensities of Gly and MI were differentiated either by analysing the short to long TE ratio of the resonance or by performing a weighted difference. Gly concentrations were compared between high-grade (WHO III-IV) and low-grade gliomas. RESULTS: High-grade gliomas showed significantly higher Gly concentrations compared to low-grade gliomas. CONCLUSION: Appropriate data processing of short and long TE (1)H MRSI provides a tool to distinguish and to quantify Gly and MI concentrations in gliomas. As Gly seems to be a marker of malignancy, more dedicated spectroscopic methods to differentiate these metabolites are justified.     

Fitting interrelated datasets: metabolite diffusion and general lineshapes

Objective

Simultaneous modeling of true 2-D spectroscopy data, or more generally, interrelated spectral datasets has been described previously and is useful for quantitative magnetic resonance spectroscopy applications. In this study, a combined method of reference-lineshape enhanced model fitting and two-dimensional prior-knowledge fitting for the case of diffusion weighted MR spectroscopy is presented.

Materials and methods

Time-dependent field distortions determined from a water reference are applied to the spectral bases used in linear-combination modeling of interrelated spectra. This was implemented together with a simultaneous spectral and diffusion model fitting in the previously described Fitting Tool for Arrays of Interrelated Datasets (FiTAID), where prior knowledge conditions and restraints can be enforced in two dimensions.

Results

The benefit in terms of increased accuracy and precision of parameters is illustrated with examples from Monte Carlo simulations, in vitro and in vivo human brain scans for one- and two-dimensional datasets from 2-D separation, inversion recovery and diffusion-weighted spectroscopy (DWS). For DWS, it was found that acquisitions could be substantially shortened.

Conclusion

It is shown that inclusion of a measured lineshape into modeling of interrelated MR spectra is beneficial and can be combined also with simultaneous spectral and diffusion modeling.

     

Lipid composition changes in normal breast throughout the menstrual cycle

The detection of breast cancer in women using magnetic resonance imaging (MR) is increasingly used as a supplement to X-ray mammography. Furthermore, proton MR spectroscopy (¹HMRS) has detected alterations in lipid profiles that are linked with tumor development and progression in human biopsy tissue. Because normal “resting” breast is highly active, it is necessary to consider that any alterations observed in lipid profiles may not be indicative of breast tumor development. The purpose of this study was to assess the changes in lipid composition in the breast throughout the menstrual cycle in “normals’ using MRS at 4.0 T. Five women with no known history of breast disease were subject to biweekly MRS breast examinations. MRS results showing water and fat resonances revealed cyclic changes in the lipid content throughout the duration of the menstrual cycle. In particular, intensity changes were seen in methylene (-CH₂-) and allylic methylene (CH₂CH₂ ^*CH=) resonances at 2.1 ppm and 1.3 ppm, respectively. These intensity changes assumed a similar cyclic trend for each subject over the 28 days that correlate with the follicular, ovulatory, and luteal phases of the menstrual cycle. The results obtained may indicate cell synthesis or metabolic activity in the breast during the menstrual cycle and provide valuable information pertinent to lipid responses associated with breast disease.     

Spurious signals in DQF spectroscopy: two-shot stimulated echoes

The most widely used technique for double-quantum filtered (DQF) single-voxel spectroscopy (SVS) is based on a symmetric PRESS sequence with two additional spatially unselective /2 pulses, one of which is usually frequency selective. The actual filtering, rejecting signals from all uncoupled resonances, can be done by suitable phase cycling of the rf pulses in successive shots, but in practice gradient filtering is always used. Under usual conditions the sequence repetition time is comparable to the spin-lattice relaxation time, and a stimulated echo is formed by five out of the ten rf pulses in two consecutive shots. This echo is not filtered out by the gradients, and additional phase cycling is needed to eliminate it. Its spatial origin is the full transverse slice selected by the last pulse of the PRESS sequence. The SVS shimming procedure may create an important field variation in this slice (outside the volume of interest VOI). Water singlet signals therefore appear in a band of frequencies other than 4.7 ppm, and remain unaffected by water suppression pulses. In practice phase-alternation schemes can reduce these spurious signals by several orders of magnitude, but even then they may mask the weak metabolite signals of interest. We describe a strategy to minimize these spurious signals and propose a 16-step phase cycling scheme that attenuates the stimulated echo in every two-step subcycle.     

High resolution magic angle spinning NMR spectroscopy for metabolic assessment of cancer presence and Gleason score in human prostate needle biopsies

Objectives  Histopathology of prostate needle biopsies (PNBs) is an important part in the diagnosis, prognosis and treatment evaluation of prostate cancer. The determination of metabolite levels in the same biopsies may have additional clinical value. Here, we demonstrate the use of non-destructive high resolution magic angle spinning (HRMAS) proton NMR Spectroscopy for the assessment of metabolic profiles of prostate tissue in PNBs as commonly obtained in standard clinical practice. Materials and methods  PNBs that were taken routinely from 48 patients suspected of having prostate cancer were subjected to HRMAS proton NMR spectroscopy. Subsequent histopathology of the same biopsies classified the tissue either as cancer (n = 10) or benign (n = 30). Results  Some practical aspects of this assessment were evaluated, such as typical spectral contamination caused by the PNB procedure. Significant metabolic differences were found between malignant and benign tissue using a small set of ratio’s involving signals of choline compounds, citrate and lactate. Moreover, significant correlations were observed between choline, total choline, and citrate over creatine signal ratios and the Gleason scores of tumor in PNBs and of tumor in the whole prostate. Conclusion  This preliminary study indicates that HRMAS NMR of routinely obtained PNBs can provide detailed metabolic information of intact prostate tissue with clinical relevance. Albert Verhofstad died before publication of this article.     

Prediction of pathological tumor volume in clinically localized prostate cancer: value of endorectal coil magnetic resonance imaging

The purpose of this study was to determine whether endorectal coil magnetic resonance imaging (MRI) enables accurate assessment of pathologic tumor volume in patients with clinically localized prostate carcinoma. Twenty-four patients with biopsy-proved prostate carcinoma underwent MRI at 0.5 T before radical prostatectomy. Tumor volumes were determined independently on axial fast-spin-echo (SE) T₂-weighted MR images and whole-mount pathology slides of the surgical specimens. At pathology, tumor volumes ranged from 0.17 to 9.42 cm³ (mean±SD, 3.11±2.99 cm³). A strong correlation (r=.944) was found between measurements of tumor volume based on MR images and pathological specimens. The error was less than 0.5 cm³ in 14 cases, in the range of 0.5–1 cm³ in 7 cases, and more than 1 cm³ in 3 cases. By using an MR tumor volume of 2 cm³ as cutoff value, extracapsular tumor spread could be predicted with a sensitivity of 81.2%, a specificity of 100%, and an accuracy of 87.5%. Tumor volume determinations based on MR images seem to be accurate enough to be helpful in clinical decision-making.     

MR imaging of the prostate in clinical practice

Magnetic resonance imaging (MRI) is the imaging tool of choice in the evaluation of prostate cancer. The main applications of MR imaging in the management of prostate cancer are: (1) to guide targeted biopsy when prostate cancer is clinically suspected and previous ultrasound-guided biopsy results are negative; (2) to localize and stage prostate cancer and provide a roadmap for treatment planning; and (3) to detect residual or locally recurrent cancer after treatment. Other MR techniques such as proton MR spectroscopic imaging (MRSI), diffusion-weighted imaging (DWI), and contrast-enhanced MRI (CE-MRI) complement conventional MR imaging by providing metabolic and functional information that can improve the accuracy of prostate cancer detection and characterization. In everyday clinical practice, and to account for patient comfort, MR imaging studies are limited to 1 h. To obtain consistently high-quality images, a well-designed protocol is necessary. Routine MR imaging can be supplemented by other MR techniques such as MRSI, DWI or CE-MRI depending on the expertise available and the clinical questions that need to be answered. This review summarizes the role of MR imaging in the management of prostate cancer and describes practical approaches to implementing anatomic, metabolic and functional MR imaging techniques in the clinic.     

In vivo lipolysis induced by heparin injection or fasting: a proton MR spectroscopy analysis of human plasma

The impact of induced lipolysis on the composition of plasma lipids is analyzed by proton magnetic resonance spectroscopy (MRS) in humans. The variations of the methylene and methyl resonances from lipids in lipoproteins are studied under two sets of lipolytic conditions: acute endovascular lipolysis induced by an intravenous injection of heparin and subacute lipolysis induced by short fasting. During acute lipolysis, the degradation of the very low density lipoproteins structures is well correlated to the modifications observed in the areas of CH₂ and CH₃ MRS signals. The comparison of regular spectra, spectra with water signal suppression, and spectra recorded with a spin-echo sequence provides information on the behavior of the different parts of the lipoproteins, that is, the neutral core, little affected by heparine-induced lipoprotein lipase (LPL) activation, and the surface layer supplying substrates to LPL. During 48 h of fasting, only limited modifications occur on the MR spectra, and lipolysis cannot be documented in details.Address for correspondence: CRMBM-CNRS, Faculté de Médecine, 27, bd Jean Moulin, 13005 Marseille, France.