Serial Precision of Metabolite Peak Area Ratios and Water Referenced Metabolite Peak Areas in Proton MR Spectroscopy of the Human Brain

doi:10.1016/S0730-725X(97)00280-4

Magnetic Resonance Imaging

Volume 16, Issue 3, April 1998, Pages 319-330

https://doi.org/10.1016/S0730-725X(97)00280-4 Get rights and content

Abstract

The precision of cerebral proton magnetic resonance spectroscopy (MRS) measurements is critical both in the clinical setting and for research purposes. Marshall et al. have recently concluded that “disappointing in vivo repeatability…is likely to limit” the ability of MRS to detect modest changes. We present here a comprehensive study of the precision of short- and long-term metabolite peak area ratios and water referenced metabolite peak areas for long echo time point resolved spectroscopy (PRESS) spectra (repetition time (TR) = 2000 ms, echo time (TE) = 136 ms) acquired from the occipital lobes of normal volunteers and a phantom using a conventional whole body 1.5 T MR system and conventional acquisition and analysis protocols. Short-term in vitro precision determined by five repeat scans on five occasions was excellent as measured by a mean coefficient of variation (NAA/Cho = 1.3%, NAA/Cr + PCr = 1.0%, Cho/Cr + PCr = 1.6%, NAA/H₂O = 0.5%, Cho/H₂O = 1.2%, Cr + PCr/H₂O = 0.8%). Long term in vitro precision using 100 spectra acquired over 2 years was also very good (NAA/Cho = 2.7%, NAA/Cr + PCr = 1.4%, Cho/Cr + PCr = 2.2%, NAA/H₂O = 1.5%, Cho/H₂O = 2.4%, Cr + PCr/H₂O = 1.5%). Short-term in vivo precision determined by five repeat scans in a single scanning session on eight subjects was also excellent (NAA/Cho = 5.2%, NAA/Cr + PCr = 3.0%, Cho/Cr + PCr = 6.6%, NAA/H₂O = 1.4%, Cho/H₂O = 4.9%, Cr + PCr/H₂O = 2.7%) and only worsened slightly for long-term in vivo precision determined by five repeat scans on eight subjects over 3 months (NAA/Cho = 5.2%, NAA/Cr + PCr = 4.8%, Cho/Cr + PCr = 7.7%, NAA/H₂O = 2.5%, Cho/H₂O = 6.4%, Cr + PCr/H₂O = 3.8%). We attribute the excellent precision reported here to the use of highly automated techniques for voxel shimming, water suppression and peak area measurements. These results allow us to repudiate Marshall’s assertion regarding disappointing repeatability of in vivo MRS.

Introduction

In vivo proton magnetic resonance spectroscopy (MRS) has important applications to the human brain, both in the clinical setting and for research purposes including epilepsy,1, 2, 3, 4multiple sclerosis,5, 6, 7brain tumours,8, 9, 10, 11dementias,12, 13, 14, 15stroke,16, 17, 18, 19and other diseases of the central nervous system.20, 21, 22, 23This list of applications and publications is illustrative rather than exhaustive, however.

Clinical magnetic resonance imaging (MRI) is still primarily a qualitative modality where images are visually interpreted by an experienced reader. Although spectra can also be read in such a way, traditionally metabolite peak area ratios have been used as a means of providing a rudimentary quantitation of spectra. The most common metabolite measurements have involved referencing to a measured resonance from the same voxel. In the event of a change or difference in ratios it is not possible to determine which of the two metabolites is responsible for the change, however.20, 27An alternative is to use a reference resonance from a contralateral voxel, or voxel from a similar area of tissue. Again, there are also some disadvantages to such an approach since the contralateral voxel may also be affected despite the presumed unilateral nature of the disease.[16]Clearly even this latter approach is not possible in the case of global metabolic defects. Absolute quantitation avoids some of the limitations associated with metabolite peak area measurements and is made possible by using either a reference standard (which is internal28, 29, 30, 31, 32or external33, 34, 35, 36, 37to the body) or the amplitude of the radiofrequency (RF) pulse required for water suppression.38, 21, 39

Successful MRS depends upon a wide variety of different factors which include patient preparation, voxel shimming, water suppression and choice of acquisition parameters and data post processing to obtain quantitative results. Each of these factors can contribute to the precision of the results obtained. High precision is especially critical for detecting temporal changes due to disease progression and/or treatment. In the clinical realm and also for research studies, it is often necessary to compare results obtained from an individual or group with normative data. In both cases, the precision of measurements is critical to help classify an individual, or to determine whether there are any significant differences between different groups of subjects.

An important factor affecting the precision of MR studies is the degree of manual interaction involved. For MRI, parameters such as the centre frequency and transmit and receive gains are normally determined by an automatic pre-scan procedure. For MRS, however, manual adjustment of a series of parameters such as linear shim offsets and water suppression tip angles is typically required for each acquisition. This manual interaction leads not only to longer scan times, but also means that great care must be taken to achieve high reproducibility using highly trained staff. Once spectra have been successfully acquired, post-processing for quantification may also require interaction, which often can be time consuming and operator dependent and may also therefore add a further random error to the results. Marshall et al. have presented a limited study of precision using a largely interactive approach,[24]some aspects of which have been recently questioned.25, 26They found coefficients of variation (CVs) for “between days” measurements of 10.1–22.6%. In the study reported here, a highly automated spectroscopy acquisition and post-processing protocol was used to avoid the commonly encountered problems described above. We show that even for measurements carried out over a period of 3 months, substantial improvements can be made, with CVs from 2.5–7.7% found.

The work reported here has comprehensively determined the short-term and long-term precision of cerebral in vivo and in vitro metabolite peak area ratios (NAA/Cho, NAA/Cr + PCr, Cho/Cr + PCr) and water referenced metabolite peak areas (NAA/H₂O, Cr + PCr/H₂O, Cho/H₂O) from single voxel proton point resolved spectroscopy (PRESS) MRS (repetition time [TR] = 2000 ms, echo time [TE] = 136 ms, voxel size = 20 × 20 × 20 mm³) over a period of up to 2 years using largely automated shimming, water suppression and post-processing techniques. Automated data analysis consisted of phase-correcting metabolite spectra using information from water reference spectra, zero-filling and Fourier transforming the data, followed by determining the areas of the unsuppressed water and NAA, Cr + PCr and Cho peaks by Levenberg-Marquardt fits to Lorentzian lineshapes. We studied short-term in vitro precision by scanning a phantom five times in a single session on five different occasions. The same phantom was scanned weekly over a period of 2 years to determine long-term in vitro precision. Short-term in vivo precision was determined using five repeat scans on seven subjects in a single session, and long-term in vivo precision determined by five repeat scans on seven subjects over a period of 3 months. Both metabolite peak area ratios and water referenced metabolite peak areas were determined for each of the four studies, and precision characterised in each case by coefficients of variation. Some of the work reported here has previously been presented in a preliminary form.[41]

Section snippets

Theory

Water referenced metabolite peak areas (metabolite peak area/water peak area) may be used as the basis for spectroscopic quantitation.28, 29, 30, 31, 32The concentration of a metabolite M, C_M, can be related to the signal from the fully relaxed metabolite (the fully relaxed peak area), S_M, and the corresponding concentration and signal for water (C_H₂O, S_H₂O). For the three principal metabolites considered here (NAA, Cr + PCr and Cho) this yields the three relationships; $C_{NAA} = C_{H_{2}O} · S_{NAA} S_{H_{2}O} · 23$ $C_{}$

Phantom and Subjects

A phantom containing in vivo levels of metabolites at concentrations found in the adult human brain was used to study in vitro precision. This “liquid brain” phantom (General Electric Medical Systems, Milwaukee, WI, USA) contains 12.50 mM NAA, 10.0 mM Cr + PCr, 3.0 mM Cho, 7.5 mM myoInositol, 12.5 mM glutamate, 12.5 mM lactate, 50.0 mM KH₂PO₄, 0.1% sodium azide and 0.1% GdDTPA, although only the NAA, Cr + PCr and Cho peaks at 2.02, 3.03 and 3.22 ppm are considered here. The metabolite

Results

The results of each study are presented here in terms of a single or mean (standard deviation) coefficient of variation. To illustrate the similarity of spectra, a figure for each study consisting of five spectra from a single subject, or the phantom, is presented. Because the system gain and centre frequency can vary slightly between studies, each spectrum was scaled to the NAA peak and baseline heights, and the NAA peaks aligned for presentation purposes.

Discussion and Conclusions

Marshall et al.[24]have carried out a study on the reproducibility of cerebral metabolite peak areas (corrected for coil loading and sensitivity) and metabolite peak area ratios obtained from a Siemens 63SP 1.5 T Magnetom MR system (Siemens AG, D-91050 Erlangen, Germany). A PRESS pulse sequence was used (TR = 1600 ms, TE = 135 ms, 256 data averages, 4096 complex data points) and data analysed using Siemens software (NUMARIS) which required manual interaction, and the authors’ own custom

Acknowledgements

We thank the radiographers of the Maudsley Hospital, particularly Caroline Andrews and Amanda Glover for their help in this study, and for suggestions from the two anonymous referees.

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Original ContributionsSerial Precision of Metabolite Peak Area Ratios and Water Referenced Metabolite Peak Areas in Proton MR Spectroscopy of the Human Brain

Abstract

Introduction

Section snippets

Theory

Phantom and Subjects

Results

Discussion and Conclusions

Acknowledgements

Magn. Reson. Imaging

Magn. Reson. Imaging

Lancet

Surg. Neurol.

Lancet

Lancet

Magn. Reson. Imaging.

Magn. Reson. Imaging.

J. Magn. Res.

Magn. Reson. Imaging.

Magn. Reson. Imaging

J. Magn. Reson.

Magn. Reson. Imaging

J. Magn. Reson. Series B

J. Magn. Reson. Series B

J. Magn. Reson.

Magn. Reson. Imaging.

Magnetic resonance spectroscopy in temporal lobe epilepsy

Neurology

Temporal lobe epilepsyPresurgical localisation with proton chemical shift imaging

Radiology

Localised in vivo proton spectroscopy in the brain of patients with multiple sclerosis

Magn. Reson. Med.

Proton magnetic resonance spectroscopy of human brain in vivo in the evaluation of multiple sclerosis. Assessment of the load of disease

Magn. Reson. Med.

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J. Comput. Assist. Tomogr.

On the interpretation of proton NMR spectra from brain tumours in vivo and in vitro

NMR Biomed.

Noninvasive differentiation of tumours with use of localised H-1 MR spectroscopy in vivo. Initial experience in patients with cerebral tumours

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Original Contributions
Serial Precision of Metabolite Peak Area Ratios and Water Referenced Metabolite Peak Areas in Proton MR Spectroscopy of the Human Brain