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PURPOSE: Advanced MRS protocols improve data quality and reproducibility relative to vendor-provided protocols, however are challenging to incorporate into the clinical workflow and require local MRS expertise for successful implementation. Here, we developed an automated advanced MRS acquisition protocol at 3T to facilitate acquisition of high-quality spectroscopic data without local MRS expertise. METHODS: First, a B(0) shimming protocol was selected for automation by comparing three widely used B(0) algorithms (two vendor protocols and FAST(EST)MAP). Next, voxel-based B(0) and B(1) calibrations were incorporated into the consensus-recommended semi-LASER sequence and combined with AutoVOI, a recently developed method for automated voxel prescription. The efficiency of collecting single-voxel data from a clinical cohort (N=40) with the automated protocol (calibration time and fraction of usable datasets) was compared with the non-automated semi-LASER protocol (N=35) whereby all prescan calibrations were executed manually in the academic hospital setting with rotating MR technologists in the neuroradiology unit. RESULTS: A multi-iteration FAST(EST)MAP protocol resulted in narrower water linewidths than vendor’s B(0) shim protocols for data acquired from six brain locations (P

Proton Magnetic Resonance Spectroscopy ((1)H MRS) provides non-invasive, quantitative metabolite profiles of tissue and has been shown to aid the clinical management of several brain diseases. Whilst most modern clinical MR scanners support MRS capabilities, routine use is largely restricted to specialized centers with good access to MR research support. Widespread adoption has been slow for several reasons, and technical challenges towards obtaining reliable good-quality results have been identified as a contributing factor. Considerable progress has been made by the research community to address many of these challenges, and in this paper a consensus is presented on deficiencies in widely available MRS methodology and validated improvements that are currently in routine use at several clinical research institutions. In particular, the localization error for the popular point resolved spectroscopy (PRESS) localization sequence was found to be unacceptably high at 3T, and the use of the semi-adiabatic localization by adiabatic selective refocusing (semi-LASER) sequence is a recommended solution. The incorporation of simulated metabolite basis-sets into analysis routines is recommended for reliably capturing the full spectral detail available from short echo time acquisitions. In addition, the importance of achieving a highly homogenous static magnetic field (B(0)) in the acquisition region is emphasized, and the limitations of current methods and hardware are discussed. Most recommendations require only software improvements, greatly enhancing the capabilities of clinical MRS on existing hardware. We anticipate the implementation of these recommendations will strengthen current clinical applications and advance progress towards developing and validating new MRS biomarkers for clinical use.

PURPOSE: To evaluate brain temperature effects of early Simian Immunodeficiency Virus (SIV) infection in rhesus macaques using proton magnetic resonance spectroscopy (MRS) thermometry and to determine whether temperature correlates with brain choline or myo-inositol levels. METHODS: Brain temperature was retrospectively determined in serial MRS scans that had been acquired at baseline and at 2 and 4 weeks post-SIV infection (wpi) in 16 monkeys by calculating the chemical shift difference between N-acetylaspartate (NAA) and water peaks in sequentially-acquired water-suppressed and un-suppressed point-resolved spectroscopy (PRESS) spectra. Frontal and parietal cortex, basal ganglia, and white matter spectra were analyzed. RESULTS: At 2 wpi, brain and rectal temperatures increased relative to baseline and normalized at 4 wpi. Brain temperatures correlated with choline levels in several brain areas but not with myo-inositol levels. CONCLUSION: These data indicate that SIV transiently increases brain temperature soon after infection and that temperature is correlated with transient changes in choline levels. As choline levels are associated with brain inflammation in SIV-infected monkeys, our findings suggest that the SIV-induced temperature increase reflects brain inflammation. We conclude that MRS thermometry may be informative in Human Immunodeficiency Virus (HIV) models and may be useful for assessing effects of treatments that reduce inflammation. This study also illustrates that existing MRS datasets containing un-suppressed water spectra can be used to measure tissue temperature, an important physiological parameter.

Proton magnetic resonance spectroscopy has emerged as one of the most informative neuroimaging modalities for studying the effect of HIV infection in the brain, providing surrogate markers by which to assess disease progression and monitor treatment. Reductions in the level of N-Acetylaspartate and N-Acetylaspartate/creatine are established markers of neuronal injury or loss. However, the biochemical basis of altered creatine levels in neuroAIDS is not well understood. This study used a rapid progression macaque model of neuroAIDS to elucidate the changes in creatine. As the disease progressed, proton magnetic resonance spectroscopy revealed a decrease in N-Acetylaspartate, indicative of neuronal injury, and an increase in creatine yet to be elucidated. Subsequently, immunohistochemistry and stereology measures of decreased synaptophysin, microtubule-associated protein 2, and neuronal density confirmed neuronal injury. Furthermore, increases in ionized calcium binding adaptor molecule 1 and glial fibrillary acidic protein indicated microglial and astroglial activation, respectively. Given these data, elevated creatine may reflect enhanced high-energy phosphate turnover in highly metabolizing activated astrocytes and microglia. Magn Reson Med, 2011. © 2011 Wiley-Liss, Inc.

Non-human primates are often used as preclinical model systems for (mostly diffuse or multi-focal) neurological disorders and their experimental treatment. Due to cost considerations, such studies frequently utilize non-destructive imaging modalities, MRI and proton MR spectroscopy ((1) H MRS). Cost may explain why the inter- and intra-animal reproducibility of the (1) H MRS observed brain metabolites, are not reported. To this end, we performed test-retest three-dimensional brain (1) H MRS in five healthy rhesus macaques at 3 T. Spectra were acquired from 224 isotropic (0.5 cm)(3) = 125 μL voxels, over 28 cm(3) (∼ 35%) of the brain, then individually phased, frequency aligned and summed into a spectrum representative of the entire volume of interest. This dramatically increases the metabolites' signal-to-noise ratios, while maintaining the (narrow) voxel linewidth. The results show that the average N-acetylaspartate, creatine, choline, and myo-inositol concentrations in the macaque brain are: 7.7 ± 0.5, 7.0 ± 0.5, 1.2 ± 0.1 and 4.0 ± 0.6 mM/g wet weight (mean ± standard deviation). Their inter-animal coefficients of variation (CV) are 4%, 4%, 6%, and 15%; and the longitudinal (intra-animal) CVs are lower still: 4%, 5%, 5%, and 4%, much better than the 22%, 33%, 36%, and 45% intra-voxel CVs, demonstrating the advantage of the approach and its utility for preclinical studies of diffuse neurological diseases in rhesus macaques.

The accuracy of metabolic quantification in MR spectroscopy is limited by the unknown radiofrequency field and T(1). To address both issues in proton ((1)H) MR spectroscopy, we obtained radiofrequency field-corrected T(1) maps of N-acetylaspartate, choline, and creatine in five healthy rhesus macaques at 3 T. For efficient use of the 4 hour experiment, we used a new three-point protocol that optimizes the precision of T(1) in three-dimensional (1)H-MR spectroscopy localization for extensive, approximately 30%, brain coverage at 0.6 x 0.6 x 0.5 cm(3) = 180-microL spatial resolution. The resulting mean T(1)s in 700 voxels were N-acetylaspartate = 1232 +/- 44, creatine = 1238 +/- 23 and choline = 1107 +/- 56 ms (mean +/- standard error of the mean). Their histograms from all 140 voxels in each animal were similar in position and shape, characterized by standard errors of the mean of the full width at half maximum divided by their means of better than 8%. Regional gray matter N-acetylaspartate, choline, and creatine T(1)s (1333 +/- 43, 1265 +/- 52, and 1131 +/- 28 ms) were 5-10% longer than white matter: 1188 +/- 34, 1201 +/- 24, and 1082 +/- 50 ms (statistically significant for the N-acetylaspartate only), all within 10% of the corresponding published values in the human brain.

The structure and metabolism of the rhesus macaque brain, an advanced model for neurologic diseases and their treatment response, is often studied noninvasively with MRI and (1)H-MR spectroscopy. Due to the shorter transverse relaxation time (T(2)) at the higher magnetic fields these studies favor, the echo times used in (1)H-MR spectroscopy subject the metabolites to unknown T(2) weighting, decreasing the accuracy of quantification which is key for inter- and intra-animal comparisons. To establish the "baseline" (healthy animal) T(2) values, we mapped them for the three main metabolites' T(2)s at 3 T in four healthy rhesus macaques and tested the hypotheses that their mean values are similar (i) among animals; and (ii) to analogs regions in the human brain. This was done with three-dimensional multivoxel (1)H-MR spectroscopy at (0.6 x 0.6 x 0.5 cm)(3) = 180 microL spatial resolution over a 4.2 x 3.0 x 2.0 = 25 cm(3) ( approximately 30%) of the macaque brain in a two-point protocol that optimizes T(2) precision per unit time. The estimated T(2)s in several gray and white matter regions are all within 10% of those reported in the human brain (mean +/- standard error of the mean): N-acetylaspartate = 316 +/- 7, creatine = 177 +/- 3, and choline = 264 +/- 9 ms, with no statistically significant gray versus white matter differences.

In vivo MR spectroscopy (MRS) studies have shown reductions in NAA/Cr levels in patients with severe neurocognitive deficits due to AIDS dementia complex (ADC), also known as neuroAIDS. The relationship between the cellular changes within the brain during neuroAIDS and the role of NAA/Cr as a metabolic marker remains unclear. In order to clarify the relationship between NAA/Cr and disease severity we utilized the simian immunodeficiency virus (SIV)/macaque model of encephalitis. High-field proton MRS was performed on extracted metabolites from frontal cortex tissue samples of 29 rhesus macaques (6 healthy, 23 moribund with AIDS). Neuropathologic determination of encephalitis severity for each animal was completed and was found to correlate with NAA/Cr levels. Decreases in Glu/Cr and GABA/Cr may indicate that both excitatory and inhibitory neurons are affected. Highly significant correlations between NAA/Cr, Glu/Cr, and GABA/Cr were observed. These neuronal metabolites were also decreased in the absence of classical SIV encephalitis (SIVE). At any disease classification, animals inoculated with SIVmac251 were found to have lower levels of NAA/Cr than animals inoculated with SIVmac239. In considering therapy for neuroAIDS the findings here support prevention of the encephalitic process, but suggest that suppressing the formation of multinucleated giant cells alone would be insufficient to prevent neuronal injury.

Insights into the pathogenesis of neurological disorders and the subsequent development of therapies for them may require preclinical trials in nonhuman primates whose brain anatomy, cellular composition, biochemistry, and physiology is similar to their human counterpart. Indeed, such models are used to study Parkinson's and Huntington's diseases (1,2), ischemic stroke (3), and neuroAIDS (4,5) among others. These models have shown similar metabolic changes to those in analogous regions of the human brain, making their use critical to our understanding of basic disease mechanisms and response to therapy. Such models may be particularly suitable to test therapeutic strategies using stem cell transplantation, trophic factors, and gene therapy (3,6). Compared with smaller animals, however, the cost and complexity of experiments in nonhuman primates severely restrict the number that can be used. Serial studies, therefore, favor nondestructive methods, such as MRI and proton MR spectroscopy/spectroscopic imaging (1H-MRS/MRSI). The latter modality allows assessment of neuronal cells, cell energetics, membrane turnover, gliosis, and glycolysis through their respective surrogate markers, N-acetylaspartate (NAA) (7), creatine (Cr) (8), choline (Cho), myo-inositol (mI), and lactate levels (9). Furthermore, since in vivo 1H-MRS has shown variable metabolic changes among different brain regions, 3D MRSI variants are clearly the technology of choice (10,11). These constraints combined with the much smaller primate brain require proportionally higher spatial resolution than the 1−8 cm3 common in humans (12,13) in order to resolve several analogous structures in the same scan. Additionally, they should be short enough to complete all the tests on an unharmed anesthetized animal. In this study, we report for the first time a 3D multi-voxel 1H-MRSI at 0.05 cm3 spatial resolution over ≈25% of the rhesus macaque brain with a 25-min acquisition time at 7T. The goal is to demonstrate that the above points are addressable with current state-of-the-art hardware, technology, and techniques.

Although the rhesus macaque brain is an excellent model system for the study of neurological diseases and their responses to treatment, its small size requires much higher spatial resolution, motivating use of ultra-high-field (B(0)) imagers. Their weaker radio-frequency fields, however, dictate longer pulses; hence longer TE localization sequences. Due to the shorter transverse relaxation time (T(2)) at higher B(0)s, these longer TEs subject metabolites to T(2)-weighting, that decrease their quantification accuracy. To address this we measured the T(2)s of N-acetylaspartate (NAA), choline (Cho), and creatine (Cr) in several gray matter (GM) and white matter (WM) regions of four healthy rhesus macaques at 7T using three-dimensional (3D) proton MR spectroscopic imaging at (0.4 cm)(3) = 64 mul spatial resolution. The results show that macaque T(2)s are in good agreement with those reported in humans at 7T: 169 +/- 2.3 ms for NAA (mean +/- SEM), 114 +/- 1.9 ms for Cr, and 128 +/- 2.4 ms for Cho, with no significant differences between GM and WM. The T(2) histograms from 320 voxels in each animal for NAA, Cr, and Cho were similar in position and shape, indicating that they are potentially characteristic of "healthy" in this species.

Proton magnetic resonance spectroscopy has emerged as one of the most informative neuroimaging modalities for studying the effect of HIV infection in the brain, providing surrogate markers by which to assess disease progression and monitor treatment. Reductions in the level of N-Acetylaspartate and N-Acetylaspartate/creatine are established markers of neuronal injury or loss. However, the biochemical basis of altered creatine levels in neuroAIDS is not well understood. This study used a rapid progression macaque model of neuroAIDS to elucidate the changes in creatine. As the disease progressed, proton magnetic resonance spectroscopy revealed a decrease in N-Acetylaspartate, indicative of neuronal injury, and an increase in creatine yet to be elucidated. Subsequently, immunohistochemistry and stereology measures of decreased synaptophysin, microtubule-associated protein 2, and neuronal density confirmed neuronal injury. Furthermore, increases in ionized calcium binding adaptor molecule 1 and glial fibrillary acidic protein indicated microglial and astroglial activation, respectively. Given these data, elevated creatine may reflect enhanced high-energy phosphate turnover in highly metabolizing activated astrocytes and microglia.

The structure and metabolism of the rhesus macaque brain, an advanced model for neurologic diseases and their treatment response, is often studied noninvasively with MRI and (1)H-MR spectroscopy. Due to the shorter transverse relaxation time (T(2)) at the higher magnetic fields these studies favor, the echo times used in (1)H-MR spectroscopy subject the metabolites to unknown T(2) weighting, decreasing the accuracy of quantification which is key for inter- and intra-animal comparisons. To establish the "baseline" (healthy animal) T(2) values, we mapped them for the three main metabolites' T(2)s at 3 T in four healthy rhesus macaques and tested the hypotheses that their mean values are similar (i) among animals; and (ii) to analogs regions in the human brain. This was done with three-dimensional multivoxel (1)H-MR spectroscopy at (0.6 x 0.6 x 0.5 cm)(3) = 180 microL spatial resolution over a 4.2 x 3.0 x 2.0 = 25 cm(3) ( approximately 30%) of the macaque brain in a two-point protocol that optimizes T(2) precision per unit time. The estimated T(2)s in several gray and white matter regions are all within 10% of those reported in the human brain (mean +/- standard error of the mean): N-acetylaspartate = 316 +/- 7, creatine = 177 +/- 3, and choline = 264 +/- 9 ms, with no statistically significant gray versus white matter differences.