Keyhole chemical exchange saturation transfer.

The keyhole technique, which involves the acquisition of dynamic data at low resolution in combination with a high-resolution reference, is developed for the purposes of chemical exchange saturation transfer (CEST) imaging, i.e., Keyhole CEST. Low-resolution data are acquired with saturation applied at different frequencies for Z-spectra, along with a high-resolution reference image taken without saturation. Three methods for high-resolution reconstruction of Keyhole CEST are evaluated using the values from quantitative high-resolution CEST maps. In addition, Keyhole CEST is applied for collection of data used for B(0) correction. The keyhole approach is evaluated for CEST contrast generation using exchanging protons in hydroxyl groups. First, the techniques are evaluated in vitro using samples of dextrose and chondroitin sulfate. Next, the work is extended in vivo to explore its applicability for gagCEST. Comparable quantitative gagCEST values are found using Keyhole CEST, provided the structure or region of interest is not limited by the low-resolution dataset.

Remission of progressive multifocal leukoencephalopathy and primary central nervous system lymphoma in an HIV-infected patient.

The coexistence of progressive multifocal leukoencephalopathy (PML) and primary central nervous system lymphoma (PCNSL) is a rare event, usually associated with a fatal outcome. We report the case of a human immunodeficiency virus (HIV)-infected individual presenting with both PML and PCNSL who made a remarkable recovery after highly active anti retroviral therapy (HAART) and radiation therapy, and discuss diagnostic and therapeutic aspects of both conditions.

In vivo near-infrared fluorescence imaging of osteoblastic activity.

In vertebrates, the development and integrity of the skeleton requires hydroxyapatite (HA) deposition by osteoblasts. HA deposition is also a marker of, or a participant in, processes as diverse as cancer and atherosclerosis. At present, sites of osteoblastic activity can only be imaged in vivo using gamma-emitting radioisotopes. The scan times required are long, and the resultant radioscintigraphic images suffer from relatively low resolution. We have synthesized a near-infrared (NIR) fluorescent bisphosphonate derivative that exhibits rapid and specific binding to HA in vitro and in vivo. We demonstrate NIR light-based detection of osteoblastic activity in the living animal, and discuss how this technology can be used to study skeletal development, osteoblastic metastasis, coronary atherosclerosis, and other human diseases.

A systematic literature review of magnetic resonance spectroscopy for the characterization of brain tumors.

BACKGROUND AND PURPOSE: Proton MR spectroscopy ((1)H-MR spectroscopy) is a potentially useful adjunct to anatomic MR imaging in the characterization of brain tumors. We performed an updated systematic review of the evidence. METHODS: We employed a standardized search strategy to find studies published during 2002-2004. We reviewed studies measuring diagnostic accuracy and diagnostic, therapeutic, or health impact of (1)H-MR spectroscopy. We abstracted information on study design, (1)H-MR spectroscopy technique, and methodologic quality. We categorized studies into 5 subgroups: (1) metastasis versus high-grade tumor; (2) high-versus low-grade tumor; (3) recurrent tumor versus radiation necrosis; (4) tumor extent; and (5) tumor versus non-neoplastic lesion. RESULTS: We identified 26 studies evaluating diagnostic performance, diagnostic impact, or therapeutic impact. No articles evaluated patient health or cost-effectiveness. Methodologic quality was mixed; most used histopathology as the reference standard but did not specify blinded interpretation of histopathology. One large study demonstrated a statistically significant increase in diagnostic accuracy for indeterminate brain lesions from 55%, based on MR imaging, to 71% after analysis of (1)H-MR spectroscopy. Several studies have found that (1)H-MR spectroscopy is highly accurate for distinguishing high- and low-grade gliomas, though the incremental benefit of (1)H-MR spectroscopy in this setting is less clear. Interpretation for the other clinical subgroups is limited by the small number of studies. CONCLUSION: The current evidence on the accuracy of (1)H-MR spectroscopy in the characterization of brain tumors is promising. However, additional high-quality studies are needed to convince policy makers. We present guidelines to help focus future research in this area.

Inhibition of lysozyme by polyvalent metal ions.

The rate of hen egg-white lysozyme (mucopeptide N-acetylmuramoylhydrolase, EC 3.2.1.17), catalysis was determined in the presence of various metal ions (Co2+, Zn2+ and eight of the trivalent lanthanide ions). In the assay system employed, the lanthanides were found to inhibit more strongly than either Zn2+ or Co2+. The inhibition data was fitted to several models of the interactions of the metal ion with the enzyme. These models ranged in complexity from a single inhibitory metal binding site on the enzyme (two-parameter fit) to the presence of two non-independent and non-equivalent inhibitory metal binding sites (five-parameter fit). The more complicated models did not fit the data more precisely than the simplest one-site model, suggesting that the adoption of the simpler model is warranted. The fact that the association constants obtained from the simplest analysis for Co2+ (1.3 +/- 1.9 . 10(2) M-1) and Gd3+ (7.0 +/- 2.6 . 10(3) M-1) are consistent with literature values determined from spectroscopic measurements further supports the validity of the simplest model.

The conformation of angiotensin II. II. The rates of peptide NH exchange with solvent for [Asn1, Val5]angiotensin II, angiotensin III and saralasin.

The amide hydrogen exchange rates in H2O of two angiotensin agonists (angiotensinamide and angiotensin III) and one angiotensin antagonist (saralasin) have been measured at room temperature by the transfer of solvent saturation method. The NH of His6 is observed to exchange more slowly than predicted for all three peptides, suggesting that it is a participant in an intramolecular hydrogen bond. The NH-C alpha H 1H-NMR coupling constants are measured and found to be constant over the pH range of 5.0 to 6.5. The results are compared with those previously obtained for human angiotensin II and interpreted in terms of a dominant three-dimensional structure common to all four molecules. Two models for this structure are evaluated using the observed NH-C alpha H coupling constants and the reported activity of conformationally restrained derivatives.

Nuclear magnetic resonance studies of the denaturation of ubiquitin.

The effects of pH, temperature and guanidine hydrochloride concentration on the structure of ubiquitin, a polypeptide which can activate adenylate cyclase and can mimic thymopoietin induced differentiation of prothymocytes, were monitored using nuclear magnetic resonance spectroscopy. This relatively small polypeptide (molecular weight of 8541) exhibits a remarkable stability towards pH and temperature changes. At 7 M guanidine hydrochloride concentration, the structure of ubiquitin is essentially a random coil.

Proton NMR investigation of Ln3+ complexes of thymopoietin 32-36.

The pentapeptide Arg-Lys-Asp-Val-Tyr (TP5) is a biologically active fragment of thymopoietin, the thymic hormone that induces selective T-cell differentiation. The formation of lanthanide(III) complexes of TP5 is demonstrated through the observation of Tb3+ fluorescence enhancement. The equilibria, stoichiometry and solution conformation of the La3+, Pr3+ and Yb3+ complexes of TP5 have been investigated using NMR spectroscopy. In addition, the dissociation constants of two methyl ester analogs of TP5 have been studied. Evidence is presented supporting an interaction between the arginine guanidino N epsilon H and the aspartate carboxylate of TP5. Binding of Ln3+ appears to be accompanied by a disruption (or weakening) of this interaction and a concomitant increase in the 180 degrees rotamer population for the aspartate carboxylate group. The observed trends in the magnitudes of the dissociation constants and the rotamer populations appear to suggest that, although a significant amount of monodentate complexes may also exist, the metal ion binds predominantly to both carboxylates in a bidentate fashion.

Transient MRI enhancement in a patient with seizures and previously resected glioma: use of MRS.

A 35-year-old man presented with partial seizures 10 years after resection of a left-sided glioblastoma multiforme. At the old operative site MRI demonstrated extensive cortical and white matter gadolinium enhancement, and PET showed hypermetabolism. Biopsy of the area was postponed when MRS showed a normal biochemical spectrum. MRI and PET abnormalities resolved after control of the seizures. MRS is noninvasive and can provide essential information in the management of patients with seizures and previously treated cerebral neoplasms.

Proton magnetic resonance spectroscopy in the frontal and temporal lobes of neuroleptic naive patients with schizophrenia.

Studies with proton magnetic resonance spectroscopy (MRS) have reported abnormalities in N-acetyl-aspartate (NAA), amino acids (AA) and choline (Cho) to creatine (Cr) ratios associated with schizophrenia. We report data on the three ratios in a sample of 18 neuroleptic naive patients with first-episode schizophrenia (eight studied in the dorsolateral prefrontal and 10 in the midtemporal lobe) and 24 healthy controls (14 studied in prefrontal and 10 in midtemporal lobes). Frontal lobe proton spectra were acquired with the stimulated-echo acquisition mode (STEAM) pulse sequence (echo time 21 ms, repetition time 2 s). Temporal lobe proton spectra were acquired with the point-resolved spectroscopy (PRESS) pulse sequence (echo time 16-21 ms, repetition time 2 s). Upon comparison with normal controls, NAA/Cr ratios were reduced in patients both for the frontal and the temporal lobe. By contrast, Cho/Cr ratios were slightly elevated in frontal and reduced in temporal lobes; whereas, AA/Cr ratios were normal in frontal and markedly increased in the temporal lobe. The reduced NAA/Cr ratios suggest lower neuronal viability in patients and is consistent with findings of reduced brain volume in both frontal and temporal regions.

Clinical magnetic resonance spectroscopy: a critical evaluation.

The present status of magnetic resonance spectroscopy (MRS) in the clinical radiology setting is discussed critically. The number of groups reporting clinical MRS results has increased, indicating the feasibility of performing localized MRS studies on current 1.5 T whole body MR imagers. However the lack of high quality radiofrequency (RF) coils for MRS and proven user-independent methods for the analysis of spectral data is still hampering further development. At present there is no consensus as to the optimal localization scheme which should be employed for phosphorus (31P) MRS. For proton MRS the stimulated echo sequence is gaining wide acceptance. The minimum voxel sizes achievable for proton and 31P MRS in the brain are calculated to be 2 and 30 cm3, respectively. The recent results obtained with proton decoupling for 31P clearly demonstrate that there is a great deal of improvement possible in the quality of localized 31P spectra at 1.5 T. Both the instrument manufacturers and researchers in the field face important challenges in translating methods which have proven feasibility in the research environment into routine clinical protocols.

Magnetic resonance imaging and magnetic resonance spectroscopy of bone tumors and bone marrow disease.

The authors have made use of an integrated magnetic resonance imaging/spectroscopy (MRI/MRS) examination to study seven patients with a variety of bone tumors. The spatial localization method used in the 31P portion of the examination was surface coil localization and a one-dimensional chemical shift imaging method (3 cases). The authors found that the precision of spatial localization was critical in many of these cases, since most of these bone tumors were surrounded by muscle tissue that contained high concentrations of phosphocreatine (PCr). For this reason, they suggest that the metabolite ratios should be referenced to the adenosine triphosphate (beta-NTP) resonance rather than PCr. The phosphate monoester (PME) to beta-NTP ratio was elevated as compared with normal muscle in all of the bone tumors studied. The authors found that all of these tumors exhibited pHs between 7.0 and 7.2, which are similar to the values found for normal muscle. They also show the feasibility of using a line-selective proton chemical shift imaging sequence with high spatial resolution for investigating changes in the fatty composition of bone marrow. This method is illustrated in an example of a patient with advanced avascular necrosis in the femoral heads.

High-resolution 1H NMR spectroscopy following experimental brain trauma.

We investigated acute metabolic changes following parasagittal fluid-percussion brain injury in the rat, using high-resolution 1H nuclear magnetic resonance (NMR) spectroscopy. Sixty minutes following brain injury or sham (surgery, no injury) treatment, brains were rapidly removed and the injured and control cortices were isolated (n = 5/group). Isolates of brain cortices were then placed in buffer and studied in a 400-MHz spectrometer with measurements taken every 15 min over a 145-min period. At the initial NMR evaluation (immediately following dissection), we observed significantly lower levels of N-acetyl aspartic acid (NAA) in the injured group compared to the sham group. Surprisingly, a reciprocal increase in the concentration of acetate, a major metabolic product of NAA, was not observed at this timepoint. At subsequent timepoints, a progressive loss of NAA was observed in both injured and sham cortices, presumably due to ischemic conditions of the ex vivo samples. However, this progressive loss of NAA was now accompanied by a commensurate accumulation of acetate. These results suggest that (1) a decrease in the concentration of NAA occurs by 1 h following experimental brain trauma, potentially marking traumatic neural injury; (2) the initial absence of an expected reciprocal increase in acetate concentration may signify rapid utilization of acetate following trauma, potentially for reparative processes; and (3) in contrast to trauma alone, post mortem ischemic conditions may induce an increase in acetate concentrations.

Magnetic resonance spectroscopy of diffuse brain trauma in the pig.

The acute metabolic events linked to the evolution of selective axonal pathology in the white matter following diffuse brain injury have not previously been evaluated due to the paucity of relevant experimental models. Here, we utilized a new model of inertial brain injury in the pig that selectively damages axons in the white matter, and applied proton and phosphorous magnetic resonance spectroscopy (MRS) to noninvasively monitor the temporal course of metabolic changes following trauma. Evaluating four pigs with MRS prior to injury, within 1 h and 3 and 7 days postinjury, we found that widespread axonal injury was produced in the absence of changes in pH, PCr/Pi, or the concentrations of ATP, and lactate. However, we did observe an acute 60% loss of intracellular Mg2+ levels, which gradually resolved by 7 days postinjury. In addition, we found that the levels of the neuron marker, N-acetylaspartate (NAA), acutely dropped 20% and remained persistently decreased for at least 7 days postinjury. Moreover, the changes in Mg2+ and NAA were found with MRS in the absence of abnormalities with conventional magnetic resonance imaging (MRI). These results show that (1) profound alterations in intracellular metabolism occur acutely following diffuse axonal pathology in the white matter, but in the absence of indicators of ischemia, and (2) axonal pathology may be evaluated with high sensitivity utilizing noninvasive MRS techniques.

New magnetic resonance imaging techniques for the evaluation of traumatic brain injury.

Although current computerized tomography (CT) and magnetic resonance imaging (MRI) techniques have shown great utility in diagnosing various aspects traumatic brain injury, damage resulting from mild diffuse brain injury often goes undetected with these procedures. Newly developed MRI techniques, including magnetization transfer imaging (MTI) and diffusion-weighted imaging (DWI), have been proposed to have enhanced sensitivities for identifying damage induced by both diffuse and focal brain injury. Results from recent initial studies with experimental models of brain injury suggest that MTI may be useful for evaluating diffuse white matter damage, while DWI may demonstrate regions of focal contusion more acutely and with greater accuracy than conventional MRI procedures.

1H spectroscopy without solvent suppression: characterization of signal modulations at short echo times.

While most proton ((1)H) spectra acquired in vivo utilize selective suppression of the solvent signal for more sensitive detection of signals from the dilute metabolites, recent reports have demonstrated the feasibility and advantages of collecting in vivo data without solvent attenuation. When these acquisitions are performed at short echo times, the presence of frequency modulations of the water resonance may become an obstacle to the identification and quantitation of metabolite resonances. The present report addresses the characteristics, origin, and elimination of these sidebands. Sideband amplitudes were measured as a function of delay time between gradient pulse and data collection, as a function of gradient pulse amplitude, and as a function of spatial location of the sample for each of the three orthogonal gradient sets. Acoustic acquisitions were performed to demonstrate the correlation between mechanical vibration resonances and the frequencies of MR sidebands. A mathematical framework is developed and compared with the experimental results. This derivation is based on the theory that these frequency modulations are induced by magnetic field fluctuations generated by the transient oscillations of gradient coils.

Water modeled signal removal and data quantification in localized MR spectroscopy using a time-scale postacquistion method.

We have previously shown the continuous wavelet transform (CWT), a signal-processing tool, which is based upon an iterative algorithm using a lorentzian signal model, to be useful as a postacquisition water suppression technique. To further exploit this tool we show its usefulness in accurately quantifying the signal metabolites after water removal. However, due to the static field inhomogeneities, eddy currents, and "radiation damping," the water signal and the metabolites may no longer have a lorentzian lineshape. Therefore, another signal model must be used. As the CWT is a flexible method, we have developed a new algorithm using a gaussian model and found that it fits the signal components, especially the water resonance, better than the lorentzian model in most cases. A new framework, which uses the two models, is proposed. The framework iteratively extracts each resonance, starting by the water peak, from the raw signal and adjusts its envelope to both the lorentzian and the gaussian models. The model giving the best fit is selected. As a consequence, the small signals originating from metabolites when selecting, removing, and quantifying the dominant water resonance from the raw time domain signal are preserved and an accurate estimation of their concentrations is obtained. This is demonstrated by analyzing (1H) magnetic resonance spectroscopy unsuppressed water data collected from a phantom with known concentrations at two different field strengths and data collected from normal volunteers using two different localization methods.

The effect of N-acetylaspartate on the intracellular free calcium concentration in NTera2-neurons.

We have studied the effect of relatively high concentrations of extracellular N-acetylaspartate (NAA) on the intracellular free calcium concentration [Ca2+]i in NTera2-neurons. While low concentrations of extracellular NAA (0.1, 1 mM) had no effect on the [Ca2+]i, high concentrations of extracellular NAA (3, 10 mM) elicited sharp and statistically significant elevations of [Ca2+]i. Different classes of antagonists of the N-methyl-D-aspartate (NMDA) receptor abolished the NAA induced elevations of the [Ca2+]i, indicating the involvement of the NMDA receptor in NAA-induced elevations of [Ca2+]i.

The effect of phospholipid vesicles on the NMR relaxation of water: an explanation for the MR appearance of the neurohypophysis?

The normal neurohypophysis is hyperintense relative to brain and adenohypophysis on T1-weighted MR images, but the signal is not chemically shifted with respect to water. The source of the hyperintense MR signal in the normal neurohypophysis has been the subject of recent controversy. To date, an adequate biophysical explanation for the unusual imaging properties of the neurohypophysis has not been found. The purpose of this study was to investigate the effect of two chemical components of the neurohypophysis, phospholipids and vasopressin, on the MR signal. We synthesized phospholipid vesicles of the same size as those found in the neurohypophysis (100-200 nm) and quantitatively measured T1, T2, and chemical shift in a spectrometer at concentrations of 0-250 mg/ml of phospholipid. Imaging of the test materials was performed on a 1.5-T whole-body MR system using T1-weighted images, T2-weighted images, reduced bandwidth, and fat suppression techniques. The experiment was also performed with saline buffer, mineral oil, vasopressin, and vasopressin incorporated into the core of the phospholipid vesicles. We found that a solution containing phospholipid vesicles has T1 and T2 characteristics analogous to the neurohypophysis and that this solution exhibits a single peak that is not chemically shifted with respect to water. Vasopressin had no effect on the signal, neither in solution nor in the vesicles. We conclude that phospholipid acts as a relaxation enhancer of water protons and that the MR characteristics of the phospholipid vesicles can account for the observed MR properties of the neurohypophysis.

Proton MR spectroscopy and magnetization transfer ratio in multiple sclerosis: correlative findings of active versus irreversible plaque disease.

PURPOSE: To characterize plaques of multiple sclerosis (MS) using both proton MR spectroscopy and magnetization transfer (MT) imaging. METHODS: The magnetization transfer ratio (MTR) was calculated from two series of three-dimensional gradient-recalled acquisition in the steady state (GRASS) images obtained with and without an MT saturation pulse. Proton spectra were acquired using the point-resolved spectroscopy (PRESS) sequence with a voxel size of 1.5 x 1.5 x 1.5 cm3. A total of 28 spectra were obtained in 13 patients who had clinically definitive MS. The spectra were analyzed together with the MTR. RESULTS: A positive relationship was found between the N-acetylaspartate (NAA)/creatine (Cr) ratio and the MTR in MS plaques, whereas no significant correlation was found between the metabolite ratios and the signal intensity on fast spin-echo T2-weighted MR images. CONCLUSION: Small changes in the MTR of MS plaques relative to the MTR of normal white matter may reflect inflammatory changes and edema, whereas larger changes in MTR correlate with decreased NAA/Cr ratio and therefore suggest demyelination and irreversible damage from chronic MS plaques.