Clinical Applications of Proton MR Spectroscopy

Mauricio Castillo, Lester Kwock, and Suresh K. Mukherji

Special Report

Magnetic resonance (MR) spectroscopy hasreceived little attention from the clinical radiol-ogy community. Indeed, most MR spectro-scopic studies are performed by a small anddedicated group of individuals, mostly basicscientists. This behavior is partly because MRspectroscopy does not produce “pictures” butresults in “graphs,” and until lately, it could onlybe obtained with dedicated units and software.At present, MR spectroscopy may be obtainedwith many clinical 1.5-T MR units and commer-cially available software. Adequate MR spectramay be obtained in periods of time as short as10 to 15 minutes. Therefore, they may be addedto routine MR imaging studies without signifi-cant time penalties. Moreover, MR spectros-copy provides greater information concerningtissue characterization than what is possiblewith MR imaging studies alone. This article willreview the current status of proton MR spectros-copy with emphasis on its clinical utility forevaluation of neurologic disorders. Also, we in-clude a section on some innovative and prom-ising uses of proton MR spectroscopy. The in-formation provided here is simplified in thehope that its understanding will lead to in-creased use of proton MR spectroscopy by clin-ical radiologists.

History

Purcell et al (1) and Bloch et al (2) elucidatedthe principles of nuclear magnetic resonance in1946. Five years later, Proctor and Yu (3) pro-posed that the resonance frequency of a nu-cleus depends on its chemical environment,which produces a small, but perceptible,change in the Larmor resonance frequency ofthat nucleus. This nuclear behavior is termed“chemical shift,” and is caused by the magneticfields generated by circulating electrons sur-

rounding the nuclei interacting with the mainmagnetic field. Protons (1H) have been tradi-tionally used for MR spectroscopy because oftheir high natural abundance in organic struc-tures and high nuclear magnetic sensitivitycompared with any other magnetic nuclei (4).Moreover, diagnostically resolvable hydrogenMR spectra may be obtained with clinical instru-ments (1.5 T or greater) and routine surfacecoils. Phosphorus 31 MR spectroscopy has alsobeen used clinically to study changes in highenergy metabolism in a number of pathologicprocesses. However, because of the scope ofthis report, phosphorus 31, carbon 13, sodium23, and fluorine 19 MR spectroscopy will not beaddressed here.

Technique

After the nuclei have been exposed to a uniformmagnetic field, they receive a 908 radio frequencypulse that rotates them from the z-axis to thex-axis. When this pulse is turned off, the nucleireturn to their original position in the z-axis. Thetime it takes them to return to their original posi-tion in the z-axis is governed by their relaxationtimes. The receiving coil detects the voltage vari-ations at many points in time during this period.This voltage variation is termed free inductiondecay and may be plotted as an exponential de-cay function (ie, intensity versus time) to yieldtime domain information (ie, relaxation times).Fourier transformation of this information yieldsinformation in the frequency domain, namely, aplot of peaks at different Larmor frequencies. Theparameters that characterize each peak includeits resonance frequency, its height, and its widthat half-height (4). The resonance frequency posi-tion of each peak on the plot is dependent on thechemical environment of that nucleus and is usu-ally expressed as parts per million from the main

From the Department of Radiology, University of North Carolina School of Medicine, Chapel Hill.Address reprint requests to Mauricio Castillo, Radiology, CB 7510, 3324 Old Infirmary, University of North Carolina at Chapel Hill, Chapel Hill, NC

27599-7510.Index terms: Brain, magnetic resonance; Magnetic resonance, spectroscopy; Magnetic resonance, tissue characterization; Special reports

AJNR 17:1–15, Jan 1996 0195-6108/96/1701–0001 q American Society of Neuroradiology

1

magnetic resonance frequency of the systemused (ie, chemical shift). The height (maximumpeak intensity) or the area under the peakmay becalculated and yield relative measurements of theconcentration of protons. The resonance frequen-cy/chemical shift position gives information re-garding the chemical environment of protons. Thewidth of the peak at half-height gives relaxationtime information because it is proportional to1/T2.Artifacts introduced by magnetic field inho-

mogeneities may result in distortion of the linewidth of the peaks and decreased ability to re-solve them. Therefore, a homogenous magneticfield is an important prerequisite to obtaining“resolvable” spectra. Shimming the field in theregion of interest to the resonance of water as-sures the homogeneity of the field. The waterline width should be less than 0.2 ppm aftershimming. Spatial localization is achieved byapplying static and/or pulsed gradients. Local-ization methods commonly used in a clinicalproton MR spectroscopy include: depth-resolved surface coil spectroscopy (DRESS),point-resolved surface coil spectroscopy(PRESS), spatially resolved spectroscopy(SPARS), and the stimulated-echo method(STEAM) (5–7). At our institution, we usePRESS and STEAM. For practical purposes,STEAM allows for shorter echo times, therebyimproving resolution of the metabolites; how-ever, it is more sensitive to motion, whereas thePRESS technique is less sensitive to motion.Because the signal from the water peak is verylarge when compared with that of other metab-olites, it needs to be suppressed for adequatevisualization of other peaks (the concentrationof water can be 10 000 times the concentrationof other metabolites). The most frequently usedmethod for suppressing the signal from water ischemical shift selective excitation (CHESS),which reduces the water signal by a factor of1000.The term voxel refers to the volume element

that is being sampled. This volume element hasa width, length, and depth. In clinical spectros-copy, the size of the voxel generally varies be-tween 2 and 8 cm3, but with current equipment,it may be as small as 1 cm3. Smaller voxelscontain smaller amounts of tissues and producelesser signal-to-noise ratios. Therefore, thenumber of signal averages required to obtaingood signal to noise needs to be increased withsmaller voxels. With voxels of 8 cm3, approxi-

2 CASTILLO

mately 100 signal averages are required to ob-tain adequate spectra. At present, most of ourMR spectroscopic studies are obtained using alocalized single volume (Fig 1). However, usingchemical-shift imaging it is possible to obtainone- or two-dimensional data sets that displaymetabolites from adjacent compartments en-compassing a large tissue volume (Fig 2). Two-dimensional chemical-shift proton MR spectros-copy allows the mapping of metaboliteconcentrations to be manipulated by computerand superimposed on the image of an abnor-mality illustrating the distribution of such me-tabolites within that area (8). Different colorsmay be assigned to each metabolite to facilitatevisual understanding of their distribution. Al-though most modern clinical MR spectroscopyunits are capable of echo times (TEs) as shortas 20 milliseconds, adequate MR spectra maybe obtained with TEs as long as 136 to 272milliseconds. Using long TEs, the signal frommost metabolites in the brain is lost except thatof choline (Cho), creatine (Cr), N-acetyl aspar-tate (NAA), and lactate. Conversely, short TEsallow for identification of many other metabo-lites (eg, myoinositol, glutamate, glutamine,and glycine). MR spectra may be obtained dur-ing a 10- to 15-minute session. Therefore, MRspectroscopy may be incorporated as part of a

Fig 1. Normal brain proton MR spectroscopy, single voxel.Proton MR spectroscopy obtained in a healthy volunteer using asingle 8-cm3 volume element in right centrum semiovale.

AJNR: 17, January 1996

Fig 2. Normal brain proton MR spec-troscopy, one-dimensional chemical-shiftimage.

A, Normal spectra obtained from adja-cent brain volumes (volumes 13 to 17).The concentration of NAA relatively in-creases in regions that contain larger areasof gray matter—in this case, the basalganglia.

B, Corresponding MR T2-weighted im-age (4000/93/1 [repetition time/TE/exci-tations]) demonstrates location of vol-umes. MR spectroscopy is shown only forvolumes 13 to 17.

AJNR: 17, January 1996 MR SPECTROSCOPY 3

routine imaging study without a significant timepenalty. At our institution, we have created a setof “shim files,” which allows the technologist toperform the study easily by setting the locationof the voxel and tailoring its size to correspondgrossly to the abnormality in question. A voxelshould include as much of the abnormality aspossible and little (generally less than 20% ofthe voxel size) normal surrounding brain.

Metabolites, Location, and Significance

There is evidence that the concentration ofnormal metabolites in the brain varies accord-ing to the patient’s age (9) (Fig 3). This varia-tion is more noticeable during the first 3 years oflife but may be seen up to 16 years of age. Themost striking variation is an increase in NAA/Crratio and a decrease in the Cho/Cr ratio as thebrain matures. These changes may reflect neu-ronal maturation and an increase in the numberof axons, dendrites, and synapses. It is unclearwhether any significant changes are observedwith advancing age.

NAA

The presence of NAA is attributable to itsN-acetyl methyl group, which resonates at 2.0ppm (Fig 1). This peak also contains contribu-tions from less-important N-acetyl groups. NAA

is accepted as a neuronal marker, and as such,its concentration will decrease with many in-sults to the brain (10). The exact role of NAA inthe brain is not known. Glutamate and N-acetyl-aspartyl-glutamate are colocalized with NAAin neurons. Breakdown of N-acetyl-aspartyl-glutamate releases both NAA and glutamate,and subsequent breakdown of NAA leads toaspartate. These compounds are excitatoryamino acids and are increased with ischemia. Itis possible that, in the near future, concentra-tions of N-acetyl-aspartyl-glutamate and gluta-mate may serve to monitor treatments designedto protect brain tissues by blocking excitatoryamino acids. NAA is not present in tumors out-side the central nervous system. Canavan dis-ease is the only disease in which NAA is in-creased. In normal spectra, NAA is the largestpeak.

Cho

The peak for Cho occurs at 3.2 ppm (Fig 1).It contains contributions from glycerophos-phocholine, phosphocholine, and phosphati-dylcholine and therefore reflects total braincholine stores. Cho is a constituent of thephospholipid metabolism of cell membranesand reflects membrane turnover, and it is aprecursor for acetylcholine and phosphatidyl-choline (10). The latter compound is used to

build cell membranes, whereas the former is acritical neurotransmitter involved in memory,cognition, and mood. Therefore, increasedCho probably reflects increased membranesynthesis and/or an increased number ofcells.

Cr

The peak for Cr is seen at 3.03 ppm andcontains contributions from Cr, Cr phosphate,and, to a lesser degree, g-aminobutyric acid,lysine, and glutathione (Fig 1). An additionalpeak for Cr may be visible at 3.94 ppm.Therefore, the Cr peak is sometimes referredto as “total Cr.” Cr probably plays a role inmaintaining energy-dependent systems inbrain cells by serving as a reserve for high-energy phosphates and as a buffer in adeno-sine triphosphate and adenosine diphosphatereservoirs (11). Cr is increased in hypometa-bolic states and decreased in hypermetabolicstates. In normal spectra, Cr is located to theimmediate right of Cho and is the third-high-est peak. Because this peak remains fairlystable even in face of disease, it may be usedas a control value.

Lactate

The lactate peak has a particular configura-tion. It consists of two distinct, resonant peakscalled a “doublet” and is caused by the mag-netic field interactions between adjacent pro-tons (J coupling). This lactate doublet occurs at

Fig 3. Normal newborn brain. Single-voxel proton MR spec-troscopy in a healthy newborn shows relatively smaller concen-tration of NAA with respect to Cho and Cr. This probably reflectsneuronal immaturity. Inositol (In) is prominent and normal at thisage.

4 CASTILLO

1.32 ppm. A second peak for lactate occurs at4.1 ppm. Because this latter peak is very closeto the water, it is generally suppressed. Nor-mally, lactate levels in the brain are low. Thepresence of lactate generally indicates that thenormal cellular oxidative respiration mecha-nism is no longer in effect, and that carbohy-drate catabolism is taking place (12). Lactatecan play a role as a neuromodulator by alteringthe excitability of local neurons (12). Confirma-tion that a peak at 1.32 ppm corresponds tolactate may be done by altering the TE. At a TEof 272 milliseconds, lactate projects above thebaseline, whereas at a TE of 136 milliseconds,the lactate doublet is inverted below the base-line.

Myoinositol

Myoinositol is a metabolite involved in hor-mone-sensitive neuroreception and is a possi-ble precursor of glucuronic acid, which detoxi-fies xenobiotics by conjugation (13). Themyoinositol peak occurs at 3.56 ppm. De-creased myoinositol content in the brain hasbeen associated with the protective action oflithium in mania and the development of dia-betic neuropathy (14). In addition, a triphos-phorylated derivative of myoinositol, myoinosi-tol-1,4,5-triphosphate, is believed to act as asecond messenger of intracellular calcium-mo-bilizing hormones (14). The combination of el-evated myoinositol and decreased NAA may beseen in patients with Alzheimer disease (15).The myoinositol peak is significant in tissuesoutside the central nervous system, for exam-ple, in head and neck carcinomas.

Glutamate and Glutamine

Glutamate is an excitatory neurotransmit-ter, which plays a role in mitochondrial me-tabolism (13). Gamma-amino butyric acid isan important product of glutamate. Glutamineplays a role in detoxification and regulation ofneurotransmitter activities (16). These twometabolites resonate closely together andthey are commonly represented by their sumas peaks located between 2.1 and 2.5 ppm.

Alanine

Alanine is a nonessential amino acid whosefunction is uncertain. Its peak occurs between

AJNR: 17, January 1996

AJNR: 17, January 1996 MR SPECTROSCOPY 5

1.3 and 1.4 ppm and therefore may be over-shadowed by the presence of lactate. Alanine,similar to lactate, inverts when the TE ischanged from 136 to 272 milliseconds.

Lipids

Membrane lipids in the brain have veryshort relaxation times and are normally notobserved unless very short TEs are used. Theprotons of lipids produce peaks at 0.8, 1.2,1.5, and 6.0 ppm. These peaks comprisemethyl, methylene, allelic, and the vinyl pro-tons of unsaturated fatty acids (17). Thesemetabolites may be increased in high-gradeastrocytomas and meningiomas and may re-flect necrotic processes (16). However, it isalso important to remember that normal lipidresonances arising from fat may be the resultof voxel contamination by fat located in thesubcutaneous scalp; they are normally muchless intense or absent at a TE of 272 millisec-onds because of their short relaxation times.

Clinical Applications

Astrocytomas

Proton MR spectroscopy readily distin-guishes normal brain tissues from astrocyto-mas (18–20). However, proton MR spectros-copy may not be able to distinguish betweendifferent histologic grades of malignancy inastrocytomas (21). Some investigators haveproposed that the presence of lactate corre-lates with a higher degree of malignancy andthat it is commonly observed in glioblastomamultiforme (8, 22). The typical proton MRspectroscopic characteristics of astrocytomasinclude a significant reduction in NAA, a mod-erate reduction in Cr, and an elevation of Cho(19) (Fig 4). Reduction of NAA probably in-dicates a loss of normal neuronal elements asthey are destroyed and/or substituted by ma-lignant cells. In astrocytomas, the NAA is re-duced to 40% to 70% of that in normal brain(10). Reduction of Cr is probably related to analtered metabolism, and elevation of Cho mayreflect increased membrane synthesis andcellularity (both of which are present in tu-mors) (8). Elevation of lactate may reflecttumor hypoxia. The Cho peak also is in-creased in the more-malignant astrocytomas(10). Proton MR spectroscopy may be used todistinguish infection from a tumor, because

the former has extremely low concentrationsof Cho (10).Proton MR spectroscopy may also play a

role in monitoring the response of astrocyto-mas to treatment (8). In some instances, pro-ton MR spectroscopy may detect tumor recur-rence before MR images become abnormal.

Meningiomas

Although the diagnosis of a meningioma isusually straightforward from the MR images,proton MR spectroscopy may be useful in dif-ficult cases. Because meningiomas arise out-side the central nervous system, theoreticallythey do not contain NAA (19). The signal ofCho is, however, markedly increased (up 300times normal) particularly in recurrent men-ingiomas (21). Lactate and alanine may bealso elevated in some meningiomas (19).There is no clear explanation for the increasein alanine in meningiomas. The above protonMR spectroscopic features are seen in typicalmeningiomas (fibrous type). Atypical andmalignant meningiomas, or those that invadethe brain, may show resonances in the loca-tion of NAA, and differentiating them fromastrocytomas may prove difficult. Unfortu-nately, in our experience, meningiomas gen-erally show MR spectra that are indistinguish-

Fig 4. Glioblastoma multiforme. Single 8-cm3 voxel from sur-gically proved glioblastoma multiforme shows low NAA andmarkedly elevated Cho. Although lactate may be present in high-grade astrocytomas, it is not seen in this tumor.

Fig 5. Meningioma.A, Axial postcontrast MR T1-weighted

image (600/15/1) shows the position of asingle voxel, which tightly fits the lesion withlittle contribution from the surroundingbrain.

B, Proton MR spectroscopy shows pat-terns similar to those seen in astrocytomaswith elevated Cho and low NAA. There is noobvious lactate or alanine. Spectra were ob-tained before contrast was given.

C, Axial precontrast MR T1-weighted im-age (770/15/1) shows location of the vol-ume of interest within a frontobasal menin-gioma (surgically proved).

D, Proton MR spectra show Cho (1), Cr(2), and a peak (A–L) at 1.3 to 1.4 ppm,corresponding to alanine and/or lactate. Nodefinite NAA is identified.

6 CASTILLO AJNR: 17, January 1996

able from those of astrocytomas and onlyrarely show the alanine peak (Fig 5). Thepresence of NAA may be related to a partialvolume-averaging artifact from adjacent brainincluded in the volume of interest. Other ex-traaxial masses, such as schwannomas, alsoshow increased lipid, lactate, and Cho peaks.

Metastases

In adults with multiple brain lesions the pri-mary differential diagnosis is that of metasta-ses. In the presence of a single lesion, differ-entiating between primary and secondarybrain tumors is important but not often possi-ble. Unfortunately, proton MR spectroscopic

findings are also nonspecific in this situation(21, 23). Metastases commonly show moder-ate to marked reduction of NAA, a decreasedCr signal, and elevated Cho (Fig 6). Obvi-ously, these features are identical to thosepresent in astrocytomas (see above). Somemetastases (particularly those from breastcarcinomas) may also contain lipids (24).Lipid resonance may also be present in high-grade astrocytomas and is caused by thepresence of necrosis. Metastases to the brainpose challenging demands to the spectrosco-pist, because their small size may requiresmall voxels and a larger number of signalaverages. If analyzed with larger voxels, whichmay include normal surrounding tissues, par-

Fig 6. Metastasis.A, Single-volume proton MR spectros-

copy in a solitary brain metastasis (provedsmall-cell carcinoma). Note decreased NAAwith respect to Cho and Cr, which appearelevated. Large peaks (small and large as-terisks) are probably combination of lactateand lipids.

B, Axial MR T2-weighted image (4000/93/1) shows the position of the voxel withrespect to the lesion. Note that the voxel iseccentric to the lesion to avoid skull andsubcutaneous fat. The tumor occupies ap-proximately 80% of the voxel.

AJNR: 17, January 1996 MR SPECTROSCOPY 7

tial volume artifacts that render the MR spec-tra suboptimal may result. In addition, be-cause of the peripheral location of theselesions, lipids from the subcutaneous scalp fatmay contaminate the sample.

Radiation injury

Histologically, radiation injury is character-ized by damage to the vascular endotheliumthat may result in ischemia and necrosis. ProtonMR spectroscopy shows elevation of lactate inpatients who have received 40 Gy or more tothe brain (25). This abnormality is appreciableeven when the MR imaging studies are normal.Therefore, proton MR spectroscopy may bepromising as a tool for the detection of radiationinjury before it becomes evident by MR imaging.Radiation necrosis may be indistinguishable

from residual and recurrent tumors by com-puted tomography, MR, single-photon emissioncomputed tomography, and even positronemission tomographic imaging (25). At our in-stitution, 25 patients with brain tumors treatedwith a combination of radiation and chemother-apy underwent serial proton MR spectroscopicstudies (Ende J, Scatliff JH, Powers S, et al,“Spectral proton and P-31 MR SpectroscopyPatterns of Treated Human Brain Tumors,” pre-sented at the 11th Annual Meeting of the Soci-ety of Magnetic Resonance in Medicine, Berlin,Germany 1992). In 9 patients with tumor recur-rence, proton MR spectroscopy showed ele-vated Cho/NAA, Cho/Cr, and the presence oflactate (Fig 7A and B). Eight patients with ra-diation necrosis showed highly depressed levelsof NAA, Cho, and Cr and an intense and broadpeak between 0 and 2.0 ppm. This peak is

consistent with tissue necrosis. This cellularbreakdown peak probably consists of free fattyacids, lactate, and amino acids (Fig 7C). Ele-vated lactate, reflecting severe tissue ischemiaand/or mitochondrial damage, was also presentin these patients.

Human Immunodeficiency Virus (HIV)Infection

In more than 60% of persons with acquiredimmunodeficiency syndrome (AIDS), a demen-tia complex will develop (26). MR imaging find-ings, which include diffuse brain atrophy andwhite matter hyperintensities in the frontopari-etal regions on T2-weighted images, are evidentonly in advanced cases. Therefore, it would beadvantageous to develop a method that maydetect the AIDS dementia complex before itbecomes evident by physical examination or byMR imaging. Proton MR spectroscopy demon-strates marked metabolic alterations in patientswith only mild AIDS-related dementia. The met-abolic abnormalities increase proportionallywith the severity of the diseases (27). Also, MRspectral abnormalities correlate with diffuse, butnot with focal, signal abnormalities on MR im-aging studies (28). In patients with AIDS de-mentia complex, proton MR spectroscopyshows a net reduction of NAA and decreases ofNAA/Cho and NAA/Cr ratios (Fig 8). In patientswith very low CD4 lymphocyte counts and ab-normal MR imaging studies of the brain, theCho/Cr ratio is increased (inferring a net in-crease in Cho) (26).HIV-infected mothers may transmit the virus

to their offspring. Approximately 25% to 40% ofthese newborns will seroconvert eventually

Fig 7. Recurrent tumor versus radiation necrosis.A, Axial MR T2-weighted image (2300/90/1) in a patient after resection of a left temporal anaplastic astrocytoma and treatment with

intraarterial chemotherapy and radiation. There is an abnormal area of increased signal intensity encompassed in volumes 19 to 24. Noenhancement was present after gadolinium administration.

B, Proton MR spectroscopy in volumes 19 to 24. The concentrations of Cho, Cr, and NAA are normal in volume 19. Volume 21 showslow NAA, high Cho, and lactate (arrow) compatible with a recurrent tumor (later proved by surgery). Volume 24 shows no NAA, low Cho,and a “death peak” (D) (combination of lactate and cellular breakdown products). At surgery, this region was necrotic brain probablyas a sequela of irradiation.

C, Single-voxel proton MR spectroscopy in a surgically proved region of radiation-induced necrosis shows large death peak.

8 CASTILLO AJNR: 17, January 1996

(29). Determining positive seroconversion dur-ing the initial 6 months of life may be difficult.Despite normal MR brain images, HIV-positivenewborns may show abnormal proton MR spec-tra as early as 10 days after birth (29). Theseabnormalities include higher NAA/Cr andCho/Cr ratios than in healthy control subjects.Also, in these patients abnormal resonances be-tween 2.1 and 2.6 ppm (overlapping the NAApeak) may be present. These have been termed“marker peaks,” and their significance is notknown.

Degenerative Disorders of the Elderly:Alzheimer and Parkinson Diseases

Alzheimer disease is a common disorder ac-counting for more than 40% of dementias in theelderly (30). Histologically, it is characterizedby neuronal loss, neurofibrillary tangles, andamyloid deposits. However, because these

changes also occur with normal aging, theyneed to be extensive before the diagnosis ofAlzheimer disease may be made with certainty.Biochemically, Alzheimer disease is character-ized by decreased cortical acetylcholine causedby a loss of cholinergic cells that are critical fornormal memory and cognition. The clinicalmanifestations of the disease may be subtle andinsidious, and often the diagnosis is difficult. Anoninvasive tool with which to diagnose earlyAlzheimer disease is therefore highly desirable.Two clinical series with a total of 76 patientswith Alzheimer disease in which proton MRspectroscopy was used to study the brain havebeen published in the radiology literature (30,31). In both studies, NAA was decreased, andmyoinositol was increased. These findings werepresent even in cases of mild to moderate de-mentia. Recently, it has been suggested that thedecrease in NAA may be caused by acutedeafferentation in the brains of patients with

AJNR: 17, January 1996 MR SPECTROSCOPY 9

Alzheimer disease, which is reflected by a trans-synaptic decrease in NAA levels (32). There-fore, proton MR spectroscopy shows promise asan early diagnostic tool for Alzheimer disease. Itremains to be determined whether Cho (reflect-ing the presence of acetylcholine) is decreasedin patients with Alzheimer disease. Other de-mentias do not commonly show alterations ofmyoinositol (30).

Fig 8. HIV infection.A, Single-voxel proton MR spectroscopy in a high-risk patient

(intravenous drug user and homosexual) who is HIV negative atthis time. (For all figures, 1 indicates Cho; 2, Cr; and 3, NAA.)

B, Single voxel (same location as A) in same patient afterseroconverting to HIV positive. The NAA has decreased relative toCho and Cr.

C, Single voxel (same location as A and B) in same patient atthe time of severe dementia and 2 weeks before death. Note themarked decrease in NAA probably related to neuronal loss ordysfunction.

Parkinson disease is characterized by re-duced activity of the electron transport chain inthe substantia nigra, platelets, and muscle (33).These findings imply that Parkinson disease is asystemic disease in which there is a dysfunctionof the mitochondrial electron transport chain. Inthese patients, NAA, Cho, and Cr are normal,but lactate is increased (33). Patients with su-perimposed dementia have a more significantelevation of lactate than do patients with iso-lated Parkinson disease.

Degenerative Disorders in Children

The clinical symptoms and imaging featuresof degenerative brain disorders presenting dur-ing childhood tend to be nonspecific. Althoughmany of these disorders have specific biochem-ical markers, a noninvasive method that pro-vides an early diagnosis and could be used tofollow up these children is desirable. Demyeli-nating childhood disorders show low NAA/Crratios (34). The lowest ratios are found in chil-dren with severe atrophy and white matterchanges. Similar proton MR spectroscopic find-ings are also present in children with neuronaldegenerative disorders. Patients with Alex-ander, Schilder, Cockayne, Leigh, and Peliza-eus-Merzbacher diseases also show decreasedNAA and elevated lactate (35). Unfortunately,these abnormalities are nonspecific and do notpermit differentiation of these disorders. Pa-tients with childhood adrenoleukodystrophyshow, by proton MR spectroscopy, decreasedNAA/Cr and increased Cho/Cr ratios (36).These patients also show elevations of the lac-tate, glutamate, glutamine, and inositol peaks.The only disorder in which proton MR spectros-copy may provide a conclusive diagnosis isCanavan disease (37, 38). These children showa marked increase of the NAA peak (Fig 9).Biochemically, this occurs because of a defi-ciency in the enzyme aspartoacyclase, whosefunction is to break down NAA. When this en-zyme does not function properly, NAA in-creases. Elevated concentration of NAAmay beat least partly responsible for the degenerationof the brain present in these patients.MELAS is a rare disorder clinically character-

ized by mitochondrial myopathy, encephalopa-thy, lactic acidosis, and strokes (39). Althoughmany children with this disorder have abnormalMR imaging findings (abnormal signal intensityin the basal ganglia and infarctions) that in the

correct clinical setting may suggest the disor-der, MELAS is a group of disorders with variableclinical expression, and in some patients, MRimaging of the brain may be normal or near-normal. In patients with this disorder, proton MRspectroscopy shows an elevation of lactate (39,40) (Fig 10). Lactate normalizes in chronic in-farctions, which also show a decrease in NAA.

Hepatic Encephalopathy

This type of encephalopathy results from cir-rhosis and other chronic liver disorders. It isclinically characterized by changes in mood andbehavior, tremors, dysarthria, dementia, andmyelopathy (41). Establishing the diagnosis ofhepatic encephalopathy with certainty in manypatients is difficult; moreover, many patientshave a subclinical form of the disease. In pa-tients with hepatic encephalopathy, proton MRspectroscopy shows an elevation of glutaminelevels and a reduction in Cho and myoinositollevels (42). Indeed, a reduction in the levels ofmyoinositol is even present in patients with liverdisease but who have no overt neurologic im-pairment (41, 42). Therefore, it may be possibleto screen for subclinical hepatic encephalopa-thy with proton MR spectroscopy.

Cerebral Ischemia

Because early and aggressive treatment (in-cluding intraarterial thrombolysis performed by

Fig 9. Canavan disease. Single-voxel proton MR spectros-copy in a patient with Canavan disease shows marked elevation ofNAA. Lac indicates lactate. (Courtesy of Drs R. A. Zimmermanand Z. Wang, Childrens Hospital of Philadelphia.)

10 CASTILLO

radiologists) of cerebral infarctions is being cur-rently evaluated, a noninvasive diagnostic testthat confirms the presence of hyperacutestrokes is desirable. Computed tomographychanges are difficult to identify during the first24 hours after the ictus. Although MR imagingabnormalities may be present as early as 3hours after the onset of symptoms, permanenttissue damage may be already present at thattime. In humans, proton MR spectroscopy per-formed in the initial 24 hours after a strokeshows elevation of lactate implying ischemia(43) (Fig 11). Decreased NAA may be ob-served as early as 4 days after infarction (44).Chronic infarctions show decreased NAA, Cr,and Cho, but no evidence of lactate (45). Ex-perimentally, an increase in lactate may be de-tected after only 2 to 3 minutes of cerebralischemia (46). In these animals, the lactate re-turned to normal when the hypoxic insult wasreversed. The role of proton MR spectroscopy inthe evaluation of human hyperacute cerebralinfarction still needs to be evaluated.White matter hyperintensities on T2-

weighted MR images are common and arefound in approximately 30% of patients olderthan 60 years of age (47). Their cause is uncer-tain but differentiating them from true infarc-tions is important. Proton MR spectroscopyshows that these age-related white matterchanges contain normal levels of NAA and Cr(48). Their Cho level is increased, suggestingan alteration of the white matter phospholipids.They do not contain lactate.

Fig 10. MELAS syndrome. Single-voxel proton MR spectros-copy over the centrum semiovale in a patient with MELAS syn-drome shows normal Cho (1), Cr (2), and NAA (3) and mildelevation of lactate (4) (from Castillo et al [39]).

AJNR: 17, January 1996

AJNR: 17, January 1996 MR SPECTROSCOPY 11

Systemic disorders, which result in centralnervous system vasculitis, may be subclinicalfor prolonged periods of time. Patients with lu-pus erythematosus have decreased NAA/Cr ra-tios (49). These ratios are lower in patients withconcomitant severe cerebral atrophy and prob-ably reflect neuronal loss.

Seizure Foci: Hippocampal Sclerosis andRasmussen Encephalitis

Hippocampal sclerosis may be pathologicallyidentified in approximately 65% of patients withtemporal lobe seizures (50). MR imaging canidentify hippocampal abnormalities in 70% ofthese patients. Visual determination of hip-pocampal abnormalities is also difficult, partic-ularly in patients with bilateral involvement.Having a noninvasive tool that could lateralizethe focus of seizures in all patients would bedesirable. Proton MR spectroscopy of the hip-pocampus is difficult to obtain because of itssmall size (which requires the use of very smallvoxels) and because of the presence of adjacentbone in the floor of the middle cranial fossa thatintroduces magnetic susceptibility artifacts. Byproton MR spectroscopy, the epileptogenic hip-pocampus shows decreased NAA/Cho ratios,an increased or a normal Cho/Cr ratio, and oc-casionally elevated lactate (51). The reductionin NAA corresponds with the neuronal loss seen

Fig 11. Acute ischemia. Single-volume proton MR spectros-copy in the right temporal region in a patient with a suspectedmiddle cerebral artery infarct. MR spectroscopy obtained within48 hours of ictus shows normal concentrations of Cho (1), Cr (2),and NAA (3). Note that in this study obtained with a TE of 136milliseconds, the lactate doublet (Lac) is inverted. NAA is normal,because neuronal loss does not occur this early.

on histology. Because these abnormalities arenot present in the normal hippocampus, abnor-mal proton MR spectra seem to be excellentmarkers for locating a seizure focus. It has beenrecently shown that shortly after the onset ofstatus epilepticus, the hippocampi may becomeswollen (Tien RD, Felsberg GJ, “The Genesis ofHuman Mesial Temporal Sclerosis after StatusEpilepticus: Evaluation with Sequential High-Resolution Fast Spin-Echo MR Imaging, pre-sented at 33rd Annual Meeting of the AmericanSociety of Neuroradiology, Chicago, 1995).This abnormality may resolve on follow-up MRimaging studies or result in hippocampal scle-rosis. Proton MR spectroscopy of the acutelyswollen hippocampus showed normal concen-trations of NAA, Cho, and Cr, but increasedlactate, suggesting that ischemia may precedeand predispose to hippocampal sclerosis.Rassmussen encephalitis is a devastating

cause of unilateral epilepsy (epilepsia partialiscontinua). As many as half of these patientshave histories of infectious diseases before theonset of seizures (52). This disorder has beenassociated with infection by the Epstein-Barrvirus and cytomegalovirus. Pathologically,there are atrophy and chronic inflammatorychanges in the involved region. MR imagingshows volume loss and areas of increased T2signal intensity, generally confined to one cere-bral hemisphere. In our experience, there is se-vere loss of NAA in the affected region by pro-ton MR spectroscopy. More importantly, wehave observed decreased NAA in contralateralcerebral hemispheres, which were normal onMR imaging. Because functional hemispherec-tomy may be indicated for the control of phar-macologically refractory seizures in these pa-tients, knowledge that abnormalities are presentin both hemispheres may preclude this type oftreatment.

Some Innovative Applications of MRSpectroscopy

Measurement of Psychoactive Drugs

The best-known application of proton MRspectroscopy for the measurement of psycho-active drugs in humans is the quantification ofbrain lithium (53). Lithium is a drug used for thetreatment of patients with bipolar disorders andprobably acts by decreasing the transport ofCho into cells (10). Measurements of serum

lithium levels do not have a clear relationship torecurrence of this disorder. Approximately 30%to 50% of patients with therapeutic serum levelsof lithium will experience a relapse each year(53). Gonzalez et al (54) have developed amethod using proton MR spectroscopy that pro-vides adequate measurement of brain lithium inhumans. This highly reliable method may playan important future role in the treatment of bi-polar disorders. It remains to be determinedwhether proton MR spectroscopy will show areduction in brain Cho levels in patients receiv-ing lithium therapy.

Neurofibromatosis Type 1

By MR imaging, approximately 43% of pa-tients with neurofibromatosis type 1 will showareas of increased T2 signal intensity in thebrain (55). These lesions tend to remain staticover time or to decrease in size. They are notmalignant, and for lack of a better term they arecalled “hamartomas.” In this group of patients,6% to 15% will develop cerebral astrocytomas.These are commonly of low histologic gradeand may be indistinguishable from the so-calledhamartomas by MR imaging alone. We havesuccessfully used proton MR spectroscopy tocharacterize these hamartomas (56). In our se-ries, 10 patients with neurofibromatosis type 1and cerebral lesions, which were presumed torepresent hamartomas (unchanged in size dur-ing a 3-year period, no mass effect or edema,and no contrast enhancement), were examinedwith localized MR spectroscopy volumes. Whenthe results obtained from the lesions were thencompared with those obtained from the brainsof healthy volunteers, no significant differenceswere found (Fig 12). This observation impliesthat lesions in patients with neurofibromatosistype 1 may be assumed to be benign when theirproton MR spectra are that of (or very close to)normal brain. Because astrocytomas have sig-nificantly different proton MR spectra than nor-mal brain (see above), they may be readilydistinguished from hamartomas. Proton MRspectroscopy also helped us characterize an en-hancing, but stable, mass in the cerebellum of achild with neurofibromatosis type 1 (57). De-spite enhancement on MR images after gado-linium administration, this lesion showed protonMR spectra identical to that of normal cerebel-lum. In this patient, this information led to theavoidance of surgery, and the lesion has re-

12 CASTILLO

mained unchanged for 4 years after its discov-ery. In a different patient with neurofibromatosistype 1 and a cerebellar mass that demonstratedgrowth in a 12-month period, proton MR spec-troscopy showed changes compatible with atumor, and resection yielded a low-grade astro-cytoma.

Cerebral Heterotopias

Small gray matter heterotopias are found inas many as 10% of children with medically re-fractory seizures (58). These are easily diag-nosed by MR images, because they parallel thesignal intensity of normal cortex in all se-quences and do not enhance after contrast ad-ministration. Rarely, these heterotopias may bevery large, and because they may contain ce-rebrospinal fluid spaces and vessels, they maybe confused with tumors. Biopsies of such le-sions will further confound the diagnosis, be-cause the pathologist may interpret them asganglion cell tumors (58). In these lesions, pro-ton MR spectroscopy may show that their me-tabolite concentrations are identical or very

Fig 12. Hamartoma in neurofibromatosis type 1. Single-volume proton MR spectroscopy in left basal ganglia hamartomain a patient with neurofibromatosis type 1 shows normal Cho (1)and Cr (2) and minimally decreased NAA (3). These findings areremarkably similar to normal brain (compare with Fig 1) and verydifferent from those expected in glial malignancies (compare withFig 4) (from Castillo et al [56]).

AJNR: 17, January 1996

Fig 13. Maxillary sinus squamous cellcarcinoma.

A, Axial MR T1-weighted image (600/15/2) shows the location of the voxel withinthe mass in the left maxillary sinus (provedsquamous cell carcinoma).

B, Proton MR spectroscopy shows ele-vated Cho with respect to Cr. S indicatessialic acid, which is present in malignanciesoutside the central nervous system; ME,methylene; and My, methyl; both are foundin membrane lipids of malignancies.

C, Axial MR T1-weighted image (600/15/2) shows the voxel encompassing theleft-sided compartment of the sphenoid si-nus. It was unclear whether the opacificationof this sinus was secondary to postobstruc-tive inflammation or tumor invasion.

D, Proton MR spectroscopy from thesphenoid sinus shows no discernible Cho orCr. A small peak for sialic acid (1) is present.A large peak (2) at 1.3 ppm may be relatedto lipids in inflammatory tissues. At surgery,there were only inflammatory mucosachanges and retained secretions in thisregion.

AJNR: 17, January 1996 MR SPECTROSCOPY 13

similar to that of normal brain, thereby estab-lishing the diagnosis of giant heterotopia(hamartomatous malformation) (17).

Multiple Sclerosis

MR images with contrast will show enhance-ment in active multiple sclerosis lesions. It hasbeen shown that NAA is decreased in patientswith chronic multiple sclerosis in whom axonalloss has occurred (59). Conversely, in acuteplaques, NAA may be normal, indicating thatthe axons have not yet disappeared or havebeen permanently damaged. In addition, reso-nances corresponding to free lipids (0.9 to 1.6ppm) have been observed in chronic multiplesclerosis plaques and may reflect disintegrationof myelin.

Malignant Head and Neck Tumors

Proton MR spectroscopy has been used tostudy orbital tumors (60, 61). Despite their rel-atively small size, adequate MR spectra may beobtained in vivo. Ocular melanotic melanomasshow a large peak at 6.72 ppm that corre-sponds to melanin (61). Preliminary data also

indicate that proton MR spectroscopy may beused to characterize extracranial head and neckmalignancies in vivo (61, 62). Lipomas showresonances at 1.29 and 2.13 ppm that corre-spond to lipids. Proton MR spectroscopy mayalso be useful in separating truly benign follic-ular thyroid masses from follicular malignancies(63). Thyroid carcinomas show resonancesfrom amino acids, glutamate (2.20 ppm), andvaline (0.71 ppm) (64).At our institution we have found that an in-

creased Cho/Cr ratio is present in all squamouscell carcinomas of the upper aerodigestive trackwhen compared with normal tissues (MukherjiSK, Schiro S, Castillo M, Kwock L, Soper R,Blackstock W, unpublished data) (Fig 13). Wehave confirmed this preliminary observation byanalyzing tissue blocks from squamous cell car-cinomas with proton MR spectroscopy at 11 T.Currently, we are evaluating the potential utilityof proton MR spectroscopy in the differentiationof recurrent and residual tumors from posttreat-ment changes, monitoring the response of tu-mors during and after treatment, attempting todetect and to characterize occult nodal metas-tases in sites that are indeterminate by both

physical examination and imaging studies, anddetecting unknown primary sites.

References1. Purcell EM, Torrey HC, Pound RV. Resonance absorption by nu-

clear magnetic moments in solids. Physiol Rev 1946;69:37–382. Bloch R, Hansen WW, Packard M. Nuclear induction. Physiol Rev

1946;69:1273. Protor WG, Yu FC. The dependence of nuclear magnetic reso-

nance frequency upon chemical shift. Physiol Rev 1950;70:7174. Lenkinski RE, Schnall MD. MR spectroscopy and the biochemical

basis of neurological disease. In: Atlas SW, ed. Magnetic Reso-nance Imaging of the Brain and Spine. New York: Raven, 1991:1099–1121

5. Bottomley PA, Foster TB, Darrow RB. Depth-resolved surface coilspectroscopy (DRESS) for in-vivo H-1, P-31, and C-13 NMR. JMagn Reson 1984;59:338–342

6. Luyten PR, Marien AJH, Systma B, et al. Solvent suppressedspatially resolved spectroscopy: an approach to high resolutionNMR on a whole body MR system. J Magn Reson 1989;9:126–131

7. Frahm J, Bruhn H, Gyngell ML, et al. Localized high resolutionproton NMR spectroscopy using stimulated echoes: initial appli-cations to human brain in vivo. Magn Reson Med 1989;9:79–93

8. Fulham MJ, Bizzi A, Dietz MJ, et al. Mapping of brain tumormetabolites with proton MR spectroscopic imaging: clinical rele-vance. Radiology 1992;185:675–686

9. van der Knaap MS, van der Grond J, van Rijen PC, et al. Age-dependent changes in localized proton and phosphorus MR spec-troscopy of the brain. Radiology 1990;176:509–515

10. Miller BL. A review of chemical issues in 1H NMR spectroscopy:N-acetyl-L-aspartate, creatine, and choline. NMR Biomed 1991;4:47–52

11. Kreis R, Ernst T, Ross BD. Development of the human brain: invivo quantification of metabolite and water content with protonmagnetic resonance spectroscopy. Magn Reson Med 1993;30:424–437

12. Sanders JA. Magnetic resonance spectroscopy. In: Orrison WW,Lewine JD, Sanders JA, Harthshorne MF, eds. Functional BrainImaging. St Louis: Mosby, 1995:419–467

13. van der Knaap MS, Ross B, Valk J. Uses of MR in inborn errors ofmetabolism. In: Kucharczyk J, Mosely M, Barkovich AJ, eds.Magnetic Resonance Neuroimaging. Boca Raton: CRC Press,1994:245–318

14. Ceodan S, Parrilla R, Santoro J, Rico M. H-1 NMR detection ofcerebral/myo-inositol. FEBS Lett 1985;187:167–172

15. Miller BL, Moats RA, Shonk T, et al. Alzheimer disease: depictionof increased cerebral myo-inositol with proton MR spectroscopy.Radiology 1993;187:433–437

16. Michealis T, Merboldt KD, Bruhn H, Dipl Math WH, Frahm J.Absolute concentrations of metabolites in the adult human brainin vivo: quantification of localized proton MR spectra. Radiology1993;187:219–227

17. Castillo M, Kwock L, Scatliff JH, Gudeman S, Greenwood R.Proton MR spectroscopic characteristics of a presumed giant sub-cortical heterotopia. AJNR Am J Neuroradiol 1993;14:426–429

18. Luyten PR, Marien AJH, Heindel W, et al. Metabolic imaging ofpatients with intracranial tumors: H-1 MR spectroscopic imagingand PET. Radiology 1990;176:791–799

19. Bruhn H, Frahm J, Gyngell ML, et al. Noninvasive differentiationof tumors with use of localized H-1 MR spectroscopy in vivo: initialexperience in patients with cerebral tumors. Radiology 1989;172:541–548

14 CASTILLO

20. Gill SS, Thomas DG, Van Bruggen N, et al. Proton MR spectros-copy of intracranial tumors: in vivo and in vitro studies. J ComputAssist Tomogr 1990;14:497–504

21. Kugel H, Heindel W, Ernestus RI, Bunke J, du Mesnil R, Fried-mann G. Human brain tumors: spectral patterns detected withlocalized H-1 MR spectroscopy. Radiology 1992;183:701–709

22. Demaerel P, Johannik K, Van Hecke P, et al. Localized H-1 NMRspectroscopy in fifty cases of newly diagnosed intracranial tu-mors. J Comput Assist Tomogr 1991;15:67–76

23. Ott D, Hennig J, Ernst T. Human brain tumors: assessment with invivo proton MR spectroscopy. Radiology 1993;186:745–752

24. Sijens PE, van Dijk P, Oudkerk M. Correlation between cholinelevel and Gd-DTPA enhancement in patients with brain metasta-ses of mammary carcinomas. Magn Reson Med 1994;32:549–555

25. Gober JR. Noninvasive tissue characterization of brain tumor andradiation therapy using magnetic resonance spectroscopy. Neu-roimaging Clin North Am 1993;3:779–802

26. Barker PB, Lee RR, McArthur JC. AIDS dementia complex: eval-uation with proton MR spectroscopic imaging. Radiology 1995;195:58–64

27. Jarvik JG, Lenkinski RE, Grossman RI, Gomori JM, Schanll MD,Frank I. Proton MR spectroscopy of HIV-infected patients: char-acterization of abnormalities with imaging and clinical correlation.Radiology 1993;186:739–744

28. Chong WK, Sweeny B, Wilkinson ID, et al. Proton spectroscopy ofthe brain in HIV infection: correlation with clinical, immunologic,and MRI findings. Radiology 1993;188:119–124

29. Cortey A, Jarvik JG, Lenkinski RE, Grossman RI, Frank I, De-livoria-Papadopoulos M. Proton MR spectroscopy of brain abnor-malities in neonates born to HIV-positive mothers. AJNR Am JNeuroradiol 1994;15:1853–1859

30. Shonk TK, Moats RA, Giffored P, et al. Probable Alzheimer dis-ease: diagnosis with proton MR spectroscopy. Radiology 1995;195:65–72

31. Miller BL, Moats RA, Shonk T, Ernst T, Woolley S, Ross BD.Alzheimer disease: depiction of increased cerebral myo-inositolwith proton MR spectroscopy. Radiology 1993;187:433–437

32. Rango M, Spagnoli D, Tomei G, Bamont F, Scarlato G, Zetta L.Central nervous system Trans-synaptic effects of acute axonalinjury: a H-1 magnetic resonance study. Magn Reson Med 1995;33:595–600

33. Bowen BC, Block RE, Sanchez-Ramos J, et al. Proton MR spec-troscopy of the brain in 14 patients with Parkinson disease. AJNRAm J Neuroradiol 1995;16:61–68

34. van der Knaap MS, van der Grond J, Luyten PR, den Hollander JA,Nauta AAP, Valk J. H-1 and P-31 magnetic resonance spectros-copy of the brain in degenerative cerebral disorders. Ann Neurol1993;31:202–211

35. Grodd W, Krageloh-Mann I, Klose U, Sauter R. Metabolic anddestructive brain disorders in children: findings with localized pro-ton MR spectroscopy. Radiology 1991;181:173–181

36. Tzika AA, Ball WS, Vigneron DB, Dunn RS, Nelson SJ, Kirks DR.Childhood adrenoleukodystrophy: assessment with proton MRspectroscopy. Radiology 1993;189:467–480

37. Marks HG, Caro PA, Wang Z, et al. Use of computed tomography,magnetic resonance imaging, and localized 1H magnetic reso-nance spectroscopy in Canavan’s disease: a case report. AnnNeurol 1991;30:106–110

38. Grodd W, Krageloh-Mann I, Petersen D, Trefz FK, Harzer K. In vivoassessment of N-acetylaspartate in brain in spongy degeneration(Canavan’s disease) by proton spectroscopy. Lancet 1990;336:437–438

AJNR: 17, January 1996

AJNR: 17, January 1996 MR SPECTROSCOPY 15

39. Castillo M, Kwock L, Green C. MELAS syndrome: imaging andproton MR spectroscopic findings. AJNR Am J Neuroradiol 1995;16:233–239

40. Barkovich AJ, Good WV, Koch TK, Berg BO. Mitochondrial dis-orders: analysis of their clinical and imaging characteristics.AJNR Am J Neuroradiol 1993;14:1119–1137

41. Kreis R, Ross BD, Farrow NA, Ackerman Z. Metabolic disorders ofthe brain in chronic hepatic encephalopathy detected with H-1 MRspectroscopy. Radiology 1992;182:19–27

42. Ross BD, Jacobson S, Villamil F, et al. Subclinical hepatic en-cephalopathy: proton MR spectroscopic abnormalities. Radiology1994;193:457–463

43. Barker PB, Gillard JH, van Zijl PCM, et al. Acute stroke: evaluationwith serial proton MR spectroscopic imaging. Radiology 1994;192:723–732

44. Bruhn H, Frahm J, Gyngell ML, Merboldt KD, Hanick W, Sauter R.Cerebral metabolism in man after acute stroke: new observationsusing localized proton MR spectroscopy. Magn Reson Med 1989;9:126–131

45. Duijn JH, Matson GB, Maudsley AA, Hugg JW, Weiner MW. Hu-man brain infarction: proton MR spectroscopy. Radiology 1992;183:711–718

46. Behar KL, den Hollander JA, Stromski ME, et al. High-resolutionH-1 nuclear magnetic resonance study of cerebral hypoxia invivo. Proc Natl Acad Sci USA 1983;80:4945–4948

47. Marshall VG, Bradley WG, Marshall CE, Bhoopat T, Rhodes RH.Deep white matter infarction: correlation of MR imaging and his-topathologic findings. Radiology 1988;167:517–522

48. Sappey-Marinier D, Calabrese G, Hetherington HP, et al. Protonmagnetic resonance spectroscopy of human brain: applicationsto normal white matter, chronic infarction, and MRI white mattersignal hyperintensities. Magn Reson Med 1992;26:313–327

49. Sibbitt WL, Haseler LJ, Griffey RH, Hart BL, Sibbitt RR, MatwiyoffNA. Analysis of cerebral structural changes in systemic lupuserythematosus by proton MR spectroscopy. AJNR Am J Neuro-radiol 1994;15:923–928

50. Kuzniecky RI, Jackson GD.Magnetic Resonance in Epilepsy. NewYork: Raven, 1995:289–314

51. Ng TC, Comair YG, Xue M, et al. Temporal lobe epilepsy: presur-gical localization with proton chemical shift imaging. Radiology1994;193:465–472

52. Kuzniecky RI, Jackson GD.Magnetic Resonance in Epilepsy. NewYork: Raven, 1995:213–324

53. Komoroski RA. Measurement of psychoactive drugs in the humanbrain in vivo by MR spectroscopy. AJNR Am J Neuroradiol 1993;14:1038–1042

54. Gonzalez RG, Guimaraes AR, Sachs GS, Rosembaum JF, Gar-wood M, Renshaw PF. Measurement of human brain lithium invivo by MR spectroscopy. AJNR Am J Neuroradiol 1993;14:1027–1037

55. Sevick RJ, Barkovich AJ, Edwards MSB, et al. Evolution of whitematter lesions in neurofibromatosis type 1: MR findings. AJR AmJ Roentgenol 1992;159:171–175

56. Castillo M, Green C, Kwock L, et al. Proton magnetic resonancespectroscopy in patients with NF-1: evaluation of hamartomasand clinical correlation. AJNR Am J Neuroradiol 1995;16:141–147

57. Castillo M, Kwock L, Green C, Schiro S, Wilson JD, Greenwood R.Proton MR spectroscopy in a possible enhancing hamartoma in apatient with neurofibromatosis type 1. AJNR Am J Neuroradiol1995;16:993–996

58. Barkovich AJ, Kjos BO. Gray matter heterotopias: MR character-istics and correlation with developmental and neurologic mani-festations. Radiology 1992;182:493–499

59. Arnold DL, Matthews PM, Francis G, Antel J. Proton magneticresonance spectroscopy of human brain in vivo in the evaluationof multiple sclerosis: assessment of the load of disease. MagnReson Med 1990;14:154–159

60. Gomori JM, Grossman RI, Shields JA, Augsburger JJ, Joseph PM,DeSimeone D. Ocular MR imaging and spectroscopy: an ex vivostudy. Radiology 1986;160:201–205

61. Mafee MF, Barany M, Gotsis ED, et al. Potential use of in vivoproton spectroscopy for head and neck lesions. Radiol Clin NorthAm 1989;27:243–254

62. McKenna WG, Lenkinski RE, Hendrix RA, Vogele KE, Bloch P.The use of magnetic resonance imaging and spectroscopy in theassessment of patients with head and neck and other superficialhuman malignancies. Cancer 1989;64:2069–2075

63. Johnson M, Selinsky B, Davis M, et al. In vitro NMR evaluation ofhuman thyroid lesions. Invest Radiol 1989;24:666–671

64. Russell P, Lean CL, Delbridge L, May GL, Dowd S, MountformdCE. Proton magnetic resonance and human thyroid neoplasia, I:discrimination between benign and malignant neoplasms. Am JMed 1994;96:383–388