1H MR Spectroscopy: Clinical Applications
Roland Kreis, Ph.D.
Department of Clinical Research, MR Spectroscopy and Methodology, University &
Inselspital, CH-3010 Bern, Switzerland
Roland KreisUniversity and InselspitalMR Center 1CH-3010 Bern
(x41) 31 632 8174
(x41) 31 382 24 86
On clinical MR systems the proton is the most widely used nucleus for applications of
magnetic resonance spectroscopy (MRS). The widespread biological applications of 1H-MRS
cannot be covered in detail, but exemplary uses will be discussed or referred to. Clinical
applications fall into two categories: clinical research vs. clinical routine, where the former
primarily aims at average responses from groups of subjects, while the latter deals with
information from a single subject - most often a single examination. In clinical and
preclinical research 1H-MRS has proven its worth many times over and there are many
applications one could refer to. For ease of availability however, research examples will
mainly be drawn from the authors own experience. 1H-MRS applications that influence
clinical decision making for an individual patient, on the other hand, are more scant and some
of the most intriguing applications will be covered. For a more detailed overview of the
literature the reader is referred to the present meeting and review articles (1-7).
The relevant methodology (i.e. methods of data acquisition, data processing, and
quantitation for reliable 1H-MRS is covered by other speakers in this course. Nevertheless I
would like to stress that the basis for successful 1H-MRS applications in the clinic has been
laid by three main developments. 1. Improvements in hardware (gradients, stability) and
techniques (rf pulses, editing methods); 2. Progress in automation (8); 3. Improvements in
data post-processing (9-12).
In order to be able to discuss clinical applications, one has to be aware of the metabolites
that can be detected on clinical MR scanners. At 1.5T, cerebral short echo-time spectra from
healthy humans show contributions from the following metabolites (resonance assignments
according to literature [Refs. in (1,13-15)] and spectra of pure compounds as reproduced in
N-acetyl methylgroups (NA) mostly from N-acetylaspartate (NAA, used as neuronal
marker (16)) and N-acetylaspartylglutamate (NAAG); methyl (Cr3) and methylene (Cr2)
protons of total creatine (Cr, i.e. creatine plus phosphocreatine); trimethylammonium groups
(TMA) mostly from choline (Ch) containing metabolites (GPC, glycerophosphorylcholine in
Fig. 1); myo-inositol (mI, suggested as glial marker (17)); glycine (Gly) corresonating with
main mI peak; glutamate (Glu) and glutamine (Gln) with both α- and β-/γ- protons forming
overlapping patterns; glucose (Glc); scyllo-inositol (sI) (18); lactate (Lac); γ-aminobutyrate
(GABA); glutathione (19), homo-carnosine (20,21), phospho-ethanolamine (22), and macro-
molecular background signals (23) most conspicuously at 0.9 and 1.5 ppm. In states of
disease or specific treatment, further metabolites are sufficiently concentrated to be detectable
and quantifiable: mobile lipids at 0.9 and 1.3 ppm; propan-1,2-diol at 1.15 ppm (24); ethanol
at 1.2 ppm; alanine at 1.5 ppm; acetate at 1.9 ppm; ketone bodies (acetone/acetoacetate) at
2.2 ppm (25,26); succinate at 2.4 ppm (27,28); taurine (Tau) at 3.3 ppm; phenylalanine at 7.3
ppm (29,30), histidine at 7.1 and 7.8 ppm (31). Further substances are detected in spectra
from other organs: carnosine (32) (7 and 8 ppm), carnitine (3.2 ppm) / acetylcarnitine (3.2,
2.13 ppm (33)), and intra- (IMCL) and extramyocellular lipids (34-36) in muscle (37-39);
citrate (2.6 ppm) in the prostate (40-42); betaine (3.25, 3.85ppm) in the kidney (43).
1H-MRS is in widespread use for the elucidation of pathophysiology starting from
investigations of cell cultures, to body fluids, to isolated organs, to whole animals, to the study
of human patients. The following examples are by no means meant to be comprehensive, but
are listed to give a flavor of current applications of 1H-MRS.
In temporal lobe epilepsy, 1H-MRS is used to lateralize the seizure focus (44-48) using a
reduction in NAA/Cr,Ch as a guide. Similarly many dementia's are characterized by
unspecific reduction of NAA levels, associated with neuronal deficits. In Alzheimer's, the
NAA deficit is accompanied by an increase in mI (49). While an NAA deficit is an ubiquitous
finding in many neurologic diseases and a mI surplus has also been found in diabetes mellitus
(25) and hemodialysis patients (50), the combination of the two abnormalities with unchanged
Cr and Ch appears to be specific to a restricted range of dementing diseases (51) and 1H-MRS
may therefore be of diagnostic value for Alzheimer's disease (49). In contrast, a decrease in
mI combined with excess Ch and Gln had earlier been found to be diagnostic in
encephalopathy associated with liver disease (52).
In stroke patients, both the reduction of NAA, as well as an increase in Lac has been
confirmed by many groups and the time course of these alterations has been documented (53-
55). It is currently of interest, whether the Lac distribution can be used to define an ischemic
Figure 1: Short-echo time PRESS spectra (TE 20ms, TR 12s) of pure metabolite solutions (25mM,37°, pH 7.05) to illustrate the spectral patterns caused by (strong) coupling, and to indicate the basisset to use if in-vivo spectra are to be decomposed into linear combinations of constituent metabolitespectra. (special thank to L. Hofmann for providing unpublished spectra)
region at risk surrounding the infarcted area (55) and whether MRS can help in prognosis (56)
and early evaluation of therapy (57). 1H-MRS has also been used extensively in patients with
tumors. While initial optimism (58) on the potential for cerebral tumor classification and
grading did not materialize readily (59), there are recent studies which are again much more
optimistic about tumor classification (60,61) and treatment monitoring (62). It appears that at
least the five most prevalent tumor types of the CNS can be distinguished by their specific
spectral appearances. It seems crucial to use chemical shift imaging to be able to judge spatial
inhomogeneities. The resulting metabolite maps can also be used for guiding subsequent
stereotactic biopsies. Additionally the work of different groups indicates that advanced
methods of data analysis (pattern recognition, linear discriminant analysis, neural networks)
(60,61,63-65) should be used to categorize the spectral patterns.
1H-MRS has proven its clinical worth also for the delineation of prostate cancer before
and after therapy (66-68).
1H-MRS is well suited to the study of pediatric diseases, in particular inborn errors of
metabolism, where enzyme defects can cause a metabolite deficit (Cr, (69)) or surplus (NAA,
(70)) or cause metabolites which are not detected normally to become prominent in the 1H-
MR spectrum (Phe, (29,30,71)).
Absolute quantitation is mandatory if pathologies are studied that are characterized by
osmolytic dysequilibria since all the metabolites observable by 1H-MRS are present in
concentrations high enough to cause relevant osmotic pressure. In fact, it is believed that mI,
GPC, Gln, Glu, Cr, and possibly NAA are among the most important compatible osmolytes
(osmolyticaly active molecules that can vary substantially in concentration without deleterious
effect (72)). It is therefore not surprising to detect major changes in cerebral metabolite
contents in patients with hypernatremia (73), chronic hyponatremia (74), and renal diseases
(50). In hypoosmolar states brain metabolite concentrations are reduced, while hyperosmolar
states lead to increased cerebral metabolite contents. Also in other diseases, MRS alterations
should always also be looked at in the light of osmotic balancing (75,76).
1H-MRS is also of great interest in studies of organ function (33,35,77-85). Visual brain
activation has been shown to cause an increase in lactate and decrease in brain glucose
(77,78,80). Recent results in 1H-MRS of working muscle indicate changes in IMCL levels
(35,83,84), Cr signals (85) and the appearance of acetylcarnitine (33).
Finally, the different roles of 1H-MRS in the clinic will be illustrated by the following
• Basic research in pathophysiology
: The most common application of MRS is illustrated
by results on the relative dynamics of blood vs. brain concentrations of Phe in phenylketonuria
• Differential diagnosis
: The use of 1H-MRS for differential diagnosis is illustrated for the
case of the classification of brain tumors (see above).
• Surgical planning, treatment assessment
: Success or partial failure of prostate cancer
therapy can be monitored by 1H-MRS with CSI of the prostate (see above).
• Treatment monitoring
: The effect of clinical treatments can be monitored by 1H-MRS.
E.g. in a study in patients with critical peripheral arterial disease, the efficacy of a new gene
therapy is monitored by 1H-MRS detection of deoxymyoglobin levels and kinetics (86).
: In near-drowning, it has been shown that 1H-MRS can provide very early
indications for the final outcome (87), and it is hoped that 1H-MRS can give the intensive care
physician reliable quantitative data on which to base the planning of the extent of therapy.
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Natl Acad Sci USA 1988:85:7836-7839.
33. Kreis R, Jung B, Rotman S, Slotboom J, Felblinger J, Boesch C. Non-invasive observation of acetyl-group
buffering by 1H-MR spectroscopy in exercising human muscle. NMR Biomed 1999:12:471-476.
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of skeletal muscle and fat tissue in vivo: Two lipid compartments in muscle tissue. Magn Reson Med1993:29:158-167.
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36. Boesch C, Kreis R. Observation of intramyocellular lipids by 1H-magnetic resonance spectroscopy. Ann N Y
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39. Kreis R, Koster M, Kamber M, Hoppeler H, Boesch C. Peak assignment in localized 1H MR spectra based on
oral creatine supplementation. Magn Reson Med 1997:37:159-163.
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44. Connelly A, Jackson GD, Duncan JS, King MD, Gadian DG. Magnetic resonance spectroscopy in temporal
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50. Michaelis T, Videen JS, Linsey MS, Ross BD. Dialysis and transplantation affect cerebral abnormalities of
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51. Ernst T, Chang L, Melchor R, Mehringer CM. Frontotemporal dementia and early Alzheimer disease:
differentiation with frontal lobe H-1 MR spectroscopy. Radiology 1997:203:829-836.
52. Kreis R, Ross BD, Farrow NA, Ackerman Z. Metabolic disorders of the brain in chronic hepatic
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brain imaging. Philos Trans R Soc Lond B Biol Sci 1999:354:1155-1163.
83. Boesch C, Decombaz J, Slotboom J, Kreis R. Observation of intramyocellular lipids by means of 1H-
magnetic resonance spectroscopy. Proc Nutr Soc 1999:58:841-850.
84. Krssak M, Petersen KF, Bergeron R, Price T, Laurent D, Rothman DL, Roden M, Shulman GI. Intramuscular
glycogen and intramyocellular lipid utilization during prolonged exercise and recovery in man: a 13C and 1Hnuclear magnetic resonance spectroscopy study. J Clin Endocrinol Metab 2000:85:748-754.
85. Kreis R, Jung B, Slotboom J, Felblinger J, Boesch C. Effect of exercise on the creatine resonances in 1H-MR
spectra of human skeletal muscle. J Magn Reson 1999:137:350-357.
86. Kreis R, Jung B, Ith M, Zwicky S, Baumgartner I, Boesch C. 1H-MR spectroscopy of deoxymyoglobin as a
tool to quantitatively evaluate tissue perfusion in healthy subjects and patients with peripheral arterialocclusive disease. MAGMA 1999: 8 (suppl):149
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studied by quantitative 1H-magnetic resonance spectroscopy: Metabolic changes and their prognostic value. JClin Invest 1996:97:1142-1154.
Final form of this Introduction was published in a Syllabus for a teaching course at the annual meeting of the"European Society of Magnetic Resonance in Medicine and Biology" in Paris, April 2000. The Syllabus isentitled "Methodology, Spectroscopy and Clinical MRI"
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