Detection of malignant tumors. Water-suppressed proton nuclear magnetic resonance spectroscopy of plasma

A sensitive and specific blood test for cancer has long been sought. The water-suppressed proton nuclear magnetic resonance (NMR) spectrum of plasma is dominated by the resonances of plasma lipoprotein lipids. We measured the mean line widths of the methyl and methylene resonances, which were found to be correlated with the presence or absence of malignant tumors. Values for the average line width were lower in patients with cancer. We analyzed plasma from 331 people (normal controls, patients with malignant and benign tumors, patients without tumors, and pregnant patients); NMR analysis and measurement of line widths were blinded to diagnosis or patient group. The mean line width for 44 normal controls (+/- SD) was 39.5 +/- 1.6 Hz. For 81 patients with untreated cancer, demonstrated by biopsy, the line width was 29.9 +/- 2.5 Hz. Patients with malignant tumors were reliably distinguished from normal controls by this method (P less than 0.0001), and differed from patients with diseases that did not involve tumors (line width, 36.1 +/- 2.6 Hz; P less than 0.0001). Patients with benign tumors (e.g., those of the breast, ovary, uterus, and colon) had line widths of 36.7 +/- 2.0 Hz and were different from those with malignant tumors (P less than 0.0001). However, pregnant patients and those with benign prostatic hyperplasia had line widths consistent with the presence of malignant tumors. The narrowing of lipoprotein-lipid resonances with cancer is consistent with the response of a host to tumor growth. We conclude that these preliminary results demonstrate that water-suppressed proton NMR spectroscopy is a potentially valuable approach to the detection of cancer and the monitoring of therapy.     

Spatial localization in nuclear magnetic resonance spectroscopy

The ability to select a discrete region within the body for signal acquisition is a fundamental requirement of in vivo NMR spectroscopy. Ideally, it should be possible to tailor the selected volume to coincide exactly with the lesion or tissue of interest, without loss of signal from within this volume or contamination with extraneous signals. Many techniques have been developed over the past 25 years employing a combination of RF coil properties, static magnetic field gradients and pulse sequence design in an attempt to meet these goals. This review presents a comprehensive survey of these techniques, their various advantages and disadvantages, and implications for clinical applications. Particular emphasis is placed on the reliability of the techniques in terms of signal loss, contamination and the effect of nuclear relaxation and J-coupling. The survey includes techniques based on RF coil and pulse design alone, those using static magnetic field gradients, and magnetic resonance spectroscopic imaging. Although there is an emphasis on techniques currently in widespread use (PRESS, STEAM, ISIS and MRSI), the review also includes earlier techniques, in order to provide historical context, and techniques that are promising for future use in clinical and biomedical applications.     

Carbon-13 nuclear magnetic resonance spectroscopy of polypropylene

The proton decoupled natural abundance ¹³C (designated as ¹³C-{¹H}) high resolution nuclear magnetic resonance spectra were measured for polypropylene at 25.1 MHz. The samples used were 4 polymers of different tacticity. The spectra of methylene carbon split corresponding to diad and partially tetrad placements. The spectra of methyl carbon of stereoblock type polymer clearly split corresponding to pentad placements. These splittings were tentatively assigned. The relation between the relative intensities of pentad placements, namely, was not satisfied. As the causes of this inequality, several possibilities were pointed out. The triad microtacticity of highly isotactic polymers determined from ¹³C-{¹H} spectra were compared with the results of n-heptane extraction and good correspondence within experimental error were obtained. The discrimination of configurational sequences of polypropylene by ¹³C-{¹H} spectra at 25.1 MHz is equal or superior to that possible in ¹H spectra at 220 MHz. However, the two peaks assigned to methine carbon showed abnormal intensities.     

Metabolic studies of the protozoan parasite, Crithidia luciliae, using proton nuclear magnetic resonance spectroscopy

Proton nuclear magnetic resonance (NMR) spectroscopy was used to follow glucose metabolism in Crithidia luciliae. Parasites were grown aerobically and anaerobically in culture, with glucose as the major carbon source and 1H NMR spectra were acquired for the cell free medium. The 1H NMR resonances of metabolites utilised and produced during cell growth were identified by difference spectroscopy, and quantitated from standard curves using 3-trimethylsilyl propionate-2,2,3,3-d4 sodium salt as an internal standard. The major metabolites produced by C. luciliae grown aerobically on 8 mM glucose were succinate, pyruvate, acetate and ethanol, in final concentrations in the media when the cells entered stationary phase of 8.5 +/- 0.5, 5.0 +/- 0.3, 2.1 +/- 0.2 and 2.5 +/- 0.6 mM, respectively. The production of succinate and pyruvate, but not acetate and ethanol, followed closely the growth curve of the parasites. Succinate was also measured enzymically and glucose using an autoanalyser. In both cases the results correlated well with the NMR data. The amounts of end products formed were greater than could be accounted for by the utilisation of glucose or any other metabolite observable in the 1H NMR spectra. There was approximately one extra atom of carbon for each molecule of succinate formed, supporting the view that succinate is produced via phosphoenolpyruvate carboxykinase and carbon dioxide fixation. Anaerobically the same major metabolites were produced, but with a decreased ratio of succinate to acetate and ethanol. The formation of glycerol from glucose was not observed under these conditions.     

Lack of efficacy of water-suppressed proton nuclear magnetic resonance spectroscopy of plasma for the detection of malignant tumors

Water-suppressed proton nuclear magnetic resonance (NMR) spectroscopy of plasma has been proposed by Fossel et al. (N Engl J Med 1986; 315:1369-76) as a technique for detecting malignant tumors. In their analysis, plasma samples from patients with cancer were clearly distinguished from those of normal subjects by measuring and averaging the methyl and methylene line widths of plasma lipoproteins in NMR spectrums. To evaluate this diagnostic procedure further, we collected and analyzed by NMR spectroscopy 145 samples of plasma from patients who served as controls, most of whom were undergoing orthopedic or cardiac surgery (n = 66); patients with a variety of untreated malignant tumors (n = 25) or treated malignant tumors (n = 18); and patients with hyperplastic or "premalignant" diseases, such as benign prostatic hyperplasia and ulcerative colitis (n = 36). All the samples were coded, and NMR spectroscopy was performed without knowledge of the patients' clinical status. There were no significant differences in the NMR line widths among the four study groups (P greater than 0.05 for all pairwise comparisons). The specificity and sensitivity of this method for distinguishing the control patients (mean line width [+/- SD], 44.0 +/- 7.4 Hz) from those with untreated cancer (43.8 +/- 6.9 Hz) were poor, with a false positive rate of 52 percent (34 of 66) and a false negative rate of 56 percent (14 of 25). Inverse correlations of line widths with age (P less than 0.01) and with the plasma triglyceride level (P less than 0.001) were detected. We conclude that NMR spectroscopy of plasma is not an accurate test for the detection of malignant tumors.     

Direct evidence of star structure from nuclear magnetic resonance spectroscopy

Until now the characterization of a star-like structure has been based on an indirect method, i.e. the comparison of the molecular weight of the star polymer and its linear precursor. By preparing well-defined and narrow-molecular-weight-distribution polybutadiene and polyisoprene stars with up to four arms — using anionic polymerization techniques and the appropriate chlorosilane — and by characterising them by means of ¹H and ¹³C NMR spectroscopy, the key point of the star, which is the core next to the silicon atom, was observed.     

Brainstem proton magnetic resonance spectroscopy in idopathic REM sleep behavior disorder

STUDY OBJECTIVES: Rapid-eye-movement (REM) sleep behavior disorder (RBD) is thought to result from a dysfunction of the brainstem structures that regulate physiologic REM sleep muscle atonia. Proton magnetic resonance spectroscopy (1H-MRS) is a noninvasive method that allows detection of in vivo neuronal dysfunction in localized brain areas. The aim of our study was to investigate whether 1H-MRS can detect brainstem abnormalities in patients with idiopathic RBD. DESIGN: 1H-MRS centered on the midbrain and the pontine tegmentum was acquired in 15 patients with idiopathic RBD and 15 control subjects matched for age and sex. SETTING: University hospital sleep laboratory center. PARTICIPANTS: Fifteen untreated patients with chronic RBD diagnosed by history and video-polysomnography, normal neurologic examination, and normal cranial MRI. Fifteen healthy controls with no sleep complaints and normal polysomnography and brain MRI. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: The metabolic peaks detectable with 1H-MRS, N-acetylaspartate (NAA), creatine-phosphocreatine (Cr), choline-containing compounds (Cho) and myoinositol (mI), and the ratios of NAA, Cho and ml to Cr were evaluated both in the midbrain and pontine tegmentum. No significant differences in N-acetylaspartate/creatine, choline/creatine and myoinosito/creatine ratios were found between patients and controls. CONCLUSIONS: The results do not suggest that marked mesopontine neuronal loss or 1H-MRS detectable metabolic disturbances occur in idiopathic RBD.     

Regional proton magnetic resonance spectroscopy patterns in dementia with Lewy bodies

Magnetic resonance spectroscopy (MRS) characteristics of dementia with Lewy bodies (DLB) Alzheimer's disease (AD) and cognitively normal controls were compared. DLB (n = 34), AD (n = 35), and cognitively normal controls (n = 148) participated in a MRS study from frontal, posterior cingulate, and occipital voxels. We investigated DLB patients with preserved hippocampal volumes to determine the MRS changes in DLB with low probability of overlapping AD pathology. DLB patients were characterized by decreased N-acetylaspartate/creatine (NAA/Cr) in the occipital voxel. AD patients were characterized by lower NAA/Cr in the frontal and posterior cingulate voxels. Normal NAA/Cr levels in the frontal voxel differentiated DLB patients with preserved hippocampal volumes from AD patients. DLB and AD patients had elevated choline/creatine, and myo-Inositol/creatine in the posterior cingulate. MRS abnormalities associated with loss of neuronal integrity localized to the occipital lobes in DLB, and the posterior cingulate gyri and frontal lobes in AD. This pattern of MRS abnormalities may have a role in differential diagnosis of DLB and in distinguishing DLB patients with overlapping AD pathology.     

Conversion of MCI to dementia: Role of proton magnetic resonance spectroscopy

Mild cognitive impairment (MCI) represents a heterogeneous group of cognitive disturbances at high risk of dementia. The amnestic subtype (aMCI) might be a prodromal state of Alzheimer's disease (AD). The aim of this study is the identification, by proton magnetic resonance spectroscopy (1H MRS), of modifications in brain metabolites able to detect subjects with aMCI at risk of conversion towards AD. Twenty-five subjects with aMCI and 29 normal elderly were enrolled; they underwent a comprehensive clinical and instrumental assessment, a cerebral 1H MRS scan to measure N-acetyl aspartate (NAA), choline (Cho), myo-inositol (mI) and creatine (Cr) in the paratrigonal white matter, bilaterally. After 1 year, 5 MCI subjects became demented (progressive MCI, pMCI). Their baseline levels of metabolites were compared with those evaluated in stable MCI (sMCI) and in controls. We observed a significant difference of the NAA/Cr ratio between pMCI (1.48+/-0.08) and sMCI (1.65+/-0.12) and between pMCI and controls (1.63+/-0.16) in the left hemisphere, suggesting that this metabolic alteration can be detected before the clinical appearance of dementia.     

High-field proton magnetic resonance spectroscopy reveals metabolic effects of normal brain aging

Altered brain metabolism is likely to be an important contributor to normal cognitive decline and brain pathology in elderly individuals. To characterize the metabolic changes associated with normal brain aging, we used high-field proton magnetic resonance spectroscopy in vivo to quantify 20 neurochemicals in the hippocampus and sensorimotor cortex of young adult and aged rats. We found significant differences in the neurochemical profile of the aged brain when compared with younger adults, including lower aspartate, ascorbate, glutamate, and macromolecules, and higher glucose, myo-inositol, N-acetylaspartylglutamate, total choline, and glutamine. These neurochemical biomarkers point to specific cellular mechanisms that are altered in brain aging, such as bioenergetics, oxidative stress, inflammation, cell membrane turnover, and endogenous neuroprotection. Proton magnetic resonance spectroscopy may be a valuable translational approach for studying mechanisms of brain aging and pathology, and for investigating treatments to preserve or enhance cognitive function in aging.     

Biochemical analysis of cervical mucus by nuclear magnetic resonance spectroscopy.

Biochemical evaluation of cervical mucus is difficult due to the characteristic rheological properties of this hydrogel. The application of high resolution nuclear magnetic resonance spectroscopy proved to be a valuable new method for differentiated biochemical analyses of human cervical mucus. A particular advantage is that it is non-destructive, that it can be applied to specimens of small volume and that no sample preparation, such as solubilization, is necessary.     

Effect of triglyceride levels on methyl and methylene envelope line widths in proton nuclear magnetic resonance spectroscopy of human plasma

Recent studies have described a relation between the line widths of the methyl and methylene resonance envelopes in the proton nuclear magnetic resonance spectrum of human plasma and the occurrence of cancer. An average line width of less than 33 Hz has been reported to correlate with the presence of cancer, whereas greater line widths have not. In 26 normal volunteers, we found a significant inverse correlation between fasting triglyceride level and plasma spectral line width. We also observed that dietary lipids have measurable effects on spectral line widths. In another sample of seven normal persons (three of whom had elevated plasma triglyceride levels), the line widths of whole plasma varied widely (mean, 35.6 +/- 8.8 Hz); however, the mean line widths of the lipoprotein fractions isolated from those samples differed greatly, but the variance within each fraction was small (very-low-density lipoprotein, 22.0 +/- 1.9 Hz; low-density lipoprotein, 35.0 +/- 2.8; high-density lipoprotein, 28.8 +/- 1.9). The results of this study indicate that the plasma triglyceride level has a profound effect on the average spectral line width of plasma. This effect can be explained by the relative amounts of lipoprotein fractions in whole plasma. Plasma triglyceride concentrations of more than 1.24 mmol per liter (greater than 110 mg per deciliter), whatever the source, produce average plasma methyl and methylene line widths of less than 33 Hz.     

Imaging central neurochemical alterations in chronic pain with proton magnetic resonance spectroscopy

Proton magnetic resonance spectroscopy has been used extensively in the study of various neurobiological disorders: depression, schizophrenia, autism, etc. But its application to chronic pain is relatively new. Not many studies in chronic pain have used (1)H-MRS. The unique ability of (1)H-MRS to assess both static and dynamic levels of glutamate and γ-aminobutyric acid (GABA) gives this method a unique position in neuroscience. Emerging evidence in chronic pain suggests an elevated excitatory/inhibitory neurotransmitter ratio is present within brain regions involved in pain processing. The combination of (1)H-MRS imaging with pharmacologic interventions holds significant promise as a direct one-to-one matching of disease pathology with drug mechanism of action can be made. As such (1)H-MRS may be useful in discovery of novel compounds for chronic pain. Research in these areas may lead to improved diagnosis and treatment of these complex patients.     

Sequence distribution of components and stereoregularity in methyl methacrylate/methyl acrylate copolymers determined by proton nuclear magnetic resonance spectroscopy

¹H-NMR spectra of methyl methacrylate/methyl acrylate copolymers obtained with radical and anionic initiators were analyzed in terms of sequence distribution of components and stereoregularity. Some rules related to the chemical shifts in triads centered with methyl methacrylate units were derived.     

Rapid identification of common human pathogens by high-resolution proton magnetic resonance spectroscopy.

Routine procedures for recovery of bacteria from clinical specimens involve culturing the latter on various nonselective and selective agar media. The bacteria are then identified by means of biochemical and immunological test procedures. Reduction of the time required to identify the bacteria is highly desirable for rapid clinical diagnosis. Towards this end the potential of proton nuclear magnetic resonance (NMR) spectroscopy for providing a "fingerprint" within the proton spectrum of five bacterial genera, reflecting their characteristic cell wall constituents, has been investigated. Establishing a database of high-resolution proton NMR spectra of a large number of bacterial species is a prerequisite for attaining this objective. A database has been established for five common human pathogens: Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus, and Enterococcus faecalis. On the basis of the presence of characteristic resonances in their spectra, a simple algorithm has been developed to differentiate and identify these microorganisms. The NMR spectra of E. coli and S. aureus showed no dependency on the type of growth medium, growth density, or incubation time.     

Absolute quantification of carnosine in human calf muscle by proton magnetic resonance spectroscopy

Carnosine has been shown to be present in the skeletal muscle and in the brain of a variety of animals and humans. Despite the various physiological functions assigned to this metabolite, its exact role remains unclear. It has been suggested that carnosine plays a role in buffering in the intracellular physiological pHi range in skeletal muscle as a result of accepting hydrogen ions released in the development of fatigue during intensive exercise. It is thus postulated that the concentration of carnosine is an indicator for the extent of the buffering capacity. However, the determination of the concentration of this metabolite has only been performed by means of muscle biopsy, which is an invasive procedure. In this paper, we utilized proton magnetic resonance spectroscopy (1H MRS) in order to perform absolute quantification of carnosine in vivo non-invasively. The method was verified by phantom experiments and in vivo measurements in the calf muscles of athletes and untrained volunteers. The measured mean concentrations in the soleus and the gastrocnemius muscles were found to be 2.81 +/- 0.57/4.8 +/- 1.59 mM (mean +/- SD) for athletes and 2.58 +/- 0.65/3.3 +/- 0.32 mM for untrained volunteers, respectively. These values are in agreement with previously reported biopsy-based results. Our results suggest that 1H MRS can provide an alternative method for non-invasively determining carnosine concentration in human calf muscle in vivo.     

Metabolite mapping of Toxocara canis using one- and two-dimensional proton magnetic resonance spectroscopy

One- and two-dimensional proton (1H) nuclear magnetic resonance (NMR) spectroscopic techniques have yielded detailed in vitro profiles of the metabolites present in the parasitic nematode Toxocara canis. The major intracellular metabolites were found to include trehalose, alanine, succinate, acetate, propionate and alpha-glycerophosphorylcholine.     

Differentiation of hydatid cyst from cysticercus cyst by proton MR spectroscopy

The metabolite patterns obtained by ex vivo proton MR spectroscopy of fluid from different locations of hydatid cysts of sheep and humans (n = 16) and cysticercus cysts of swine and humans (n = 25) were compared with an objective of differentiating the two parasites on the basis of their metabolite pattern. The spectra from hydatid fluid differed from cysticercus cyst by the absence of creatine in the former. When the hydatid cyst was fertile, malate and/or fumarate was also observed, which was absent in cysticercus cyst. The most likely explanation for the presence of creatine only in the cysticercus fluid is its active diffusion from the surrounding host tissue along with a contribution from the musculature present in the bladder wall of the cyst.