CONSIDERACIONES PREVIAS

NMR spectral information has been used to enrich chemistry for the past 40 years; it is just now attracting the interest of the medical com-munity. With the application of in vivo MRS, it is possible to obtain various spectra from patients and therefore gain information about the chemistry of life. Progress toward clinical utility is slow, but the rate of progress is increasing.

Hydrogen

The in vivo MR hydrogen spectrum is domi-nated by the signal from water. The second most common contributor to the MR signal is the triglycerides found in adipose tissue (fat).

Depending on the location of the volume of interest, fat may be the only tissue present,

though water is usually evident. The strong (at least in the NMR world) signal from the hydro-gen nucleus makes this nuclide the one of choice for MRI.

MRI is relatively easy when the dominant signal is from the hydrogen in water. Image quality is compromised when fat is present.

However, the presence of these two signals only causes problems at high magnetic field strength.

At low magnetic field strength the difference between the fat signal and water signal is small enough that it is overwhelmed by the gradient magnetic fields used to make the image.

At higher magnetic fields this difference is not overwhelmed by the gradient magnetic fields, and distinct fat and water images that are slightly offset from each other are pro-duced. The resulting image contains a chemical shift artifact (Figure 9-10). The fat and water

Figure 9-10 The observed curvilinear rim of decreased signal intensity adjacent to the renal cortex is an artifact caused by the chemical shift between hydrogen in fat and hydro-gen in water. (Courtesy George Oliver, St. Louis, MO.)

signals are 10,000 times stronger than the sig-nal from other hydrogen-containing metabo-lites. The use of hydrogen NMR to study these metabolites is thus a strong challenge.

Currently, the use of fat and water suppres-sion (i.e., removing these signals from the MRS region of interest) permits the noninvasive observation of at least 15 different metabolites in the brain. The MRS conditions for conven-ient measurement select signals from N-acetyl aspartate, creatine, phosphocreatine, choline, and lactate. The lactate is often used as an indicator of a pathologic condition, whereas the other compounds are found in most sub-jects. The database for ¹H MRS is accumulating rapidly. The widespread diffusion of this data-base will encourage the clinical use of MRS in the future.

Phosphorus

Another nuclide currently receiving attention in MRS is the phosphorus isotope ³¹P. This nuclide is the only one of phosphorus found in nature. Phosphorus is present in all human tis-sue and is a reporter of metabolism. It has a spin quantum number of ¹⁄₂ and is similar in its spectral properties to hydrogen. In other words, it is well behaved in its MR spectral properties.

One important phosphorus-containing metabolite is adenosine triphosphate (ATP).

Others include adenosine diphosphate (ADP), a byproduct of ATP metabolism, and adenosine monophosphate (AMP), a building block for the formation of ADP and ATP. Creatine phos-phate (PCr), a chemical intermediate for the storage of biochemical energy, is also evident in the ³¹P MR spectrum from some tissues.

All of these metabolites enter into reactions in which phosphoric acid, known to physiolo-gists as inorganic phosphate (Pi), is either formed or consumed. One interesting applica-tion of ³¹P MRS is to determine the intracellu-lar pH from the chemical shift of the inorganic phosphate signal. Thus the MR spectrometer is a sophisticated, expensive, but noninvasive pH meter.

An overlay of all these phosphorus signals appears in the MR spectrum of most tissues and provides a window into the energy state of the tissue. A representative ³¹P spectrum is shown in Figure 9-11.

Phosphorus MR is being used to understand and perhaps diagnose metabolic disorders, assess damage in heart attacks, and monitor the effects of drugs and drug therapy.

Carbon

Almost every chemical compound in living systems contains the carbon atom. Therefore it is anticipated that any method to observe car-bon with MR spectroscopy would be advanta-geous. Nature has conspired to provide carbon in an NMR silent form.

The ordinary nuclide of carbon, ¹²C, is non-magnetic because it has paired nucleons and therefore does not generate an NMR spectrum.

The magnetic form of carbon, ¹³C, is present in all tissue to the extent of 1.1%. A number of laboratories are studying this scarce nucleus, though the studies are experimen-tally demanding.

Figure 9-11 A representative ³¹P nuclear magnetic resonance spectrum. (Courtesy Bud Wendt, Houston, TX.)

The scarcity of ¹³C permits the tagging of experimental molecules by as much as 100-fold. The tagged molecules can be fol-lowed through a number of interesting and intricate metabolic events with MRS. A repre-sentative ¹³C NMR spectrum is shown in Figure 9-12.

Sodium

Sodium is abundant in the body primarily as sodium chloride and other salts. The common isotope of sodium is ²³Na; its spin quantum number is ³⁄₂. A spectrum of ²³Na is shown in Figure 9-13. There are indications that the MR signal of sodium can be used to probe the

intramolecular and intermolecular environments of the molecule and to report them separately.

Fluorine

Fluorine has two advantages for observation in human tissue. Its gyromagnetic ratio is nearly as great as that of hydrogen, and the only nuclear species is ¹⁹F, with a spin of ¹⁄₂. Atom for atom, it is as easy to observe as hydrogen. However, it is almost totally absent from the human body.

Indeed, high concentrations of fluorine can be toxic.

In the event a safe agent can be identified, which does occur, fluorine becomes a nearly perfect tracer, or indicator, of metabolism. In a

ppm

0 40

80 120

160 200

Figure 9-12 A representative ¹³C nuclear magnetic resonance spectrum. (Courtesy Bud Wendt, Houston, TX.)

200 Hz

Figure 9-13 A representative ²³Na nuclear magnetic resonance spectrum. (Courtesy Bud Wendt, Houston, TX.)

typical measurement there would be no ¹⁹F before the measurement, the agent would be introduced, and the arrival of ¹⁹F at the volume of interest can be monitored.

In the vocabulary of imaging these are dark field measurements. There is no signal at the beginning and then an abundant signal as the

19F arrives at the observation site. Figure 9-14 shows experimental ¹⁹F images focused on blood substitute materials and pO₂imaging.

Forms of materials that carry ¹⁹F are the new perfluorocarbon artificial bloods and 5-deoxyfluoroglucose (5-FDG). In addition, chemotherapeutic agents for the treatment of cancer often carry ¹⁹F in their chemical struc-ture. Research is being conducted in the use of these agents to monitor blood flow, follow

metabolism, and understand the effectiveness of cancer therapy regimens.

Nitrogen

Nitrogen is nearly as common in biology as carbon. All amino acids, peptides, proteins, deoxyribonucleic acids (DNA), and ribonucleic acids (RNA) are rich in nitrogen. Ordinary nitrogen is ¹⁴N, with a spin quantum number of 1. The observation of this nuclide is diffi-cult. It has an unfavorable gyromagnetic ratio and is inherently insensitive. In addition the spectral lines are usually extremely broad and hard to detect.

A rare nuclide of nitrogen, ¹⁵N, has a spin of

¹⁄₂ and would seem to be suitable for study.

However, its gyromagnetic ratio is also

Figure 9-14 Images through the midtorso of a pig. A, Sow image. B, ¹⁹F spin echo image. C, Calculated pO₂ T1 weighted (T1W) ¹⁹F image during normal breathing.

D, Calculated pO₂T1W ¹⁹F image during 100% oxygen breathing. (Courtesy Stephen Thomas, Cincinnati, OH.)

A

C

B

D

unfavorable, and its observation is exceedingly difficult. If nitrogen is to be useful in medicine, it will require expensive ¹⁵N-enriched sub-strates and long observation times.

CHALLENGE QUESTIONS

1. The distribution of frequencies observed in an MR signal is known as what quantity?

2. List at least three other elements that could possibly be used to make a magnetic resonance (MR) image.

3. What happens to the appearance of an NMR spectrum at high magnetic field strength?

4. What is J-coupling?

5. What is chemical shift as it relates to NMR spectroscopy?

6. What is the variation in magnetic field homogeneity expressed in parts per million for a 1 T ± 10 µ T magnet?

7. What is the chemical shift difference in the resonant frequency between fat and water protons?

8. What is the gyromagnetic ratio for hydrogen?

9. What is the frequency difference for proton spins in water versus those in fat at 1.5 T?

10. Along which axis does the chemical shift artifact appear?

Part II