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Amsm.dkf.unibe.ch

1H MR Spectroscopy: Clinical Applications
Roland Kreis, Ph.D.
Department of Clinical Research, MR Spectroscopy and Methodology, University & Inselspital, CH-3010 Bern, Switzerland Correspondence to: 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).
Specific Examples 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 patients (71).
• 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).
• Prognosis: 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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19. Trabesinger AH, Weber OM, Duc CO, Boesiger P. Detection of glutathione in the human brain in vivo by means of double quantum coherence filtering. Magn Reson Med 1999:42:283-289.
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25. Kreis R, Ross BD. Cerebral metabolic disturbances in patients with subacute and chronic diabetes mellitus: Detection with proton MR spectroscopy. Radiology 1992:184:123-130.
26. Seymour KJ, Bluml S, Sutherling J, Sutherling W, Ross BD. Identification of cerebral acetone by 1H-MRS in patients with epilepsy controlled by ketogenic diet. MAGMA 1999:8:33-42.
27. Kohli A, Gupta RK, Poptani H, Roy R. In vivo proton magnetic resonance spectroscopy in a case of intracranial hydatid cyst. Neurology 1995:45:562-564.
28. Kreis R, Bigler P, Gottstein B, Boesch C. 1H-MRS of Ecchinococcus granulosus cysts: Succinate, not pyruvate is the characteristic marker substance. in "Proc., 6th Meeting of the ISMRM; Sydney, 1998," p.
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30. Novotny EJ, Jr., Avison MJ, Herschkowitz N, Petroff OAC, Prichard JW, Seashore R, Rothman DL. In vivo measurement of phenylalanine in human brain by proton nuclear magnetic resonance spectroscopy. PediatrRes 1995:37:244-249.
31. Vermathen P, Capizzano AA, Maudsley AA. Administration and (1)H MRS detection of histidine in human brain: application to in vivo pH measurement. Magn Reson Med 2000:43:665-675.
32. Pan JW, Hamm JR, Rothman DL, Shulman RG. Intracellular pH in human skeletal muscle by 1H NMR. Proc 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.
34. Schick F, Eismann B, Jung WI, Bongers H, Bunse M, Lutz O. Comparison of localized proton NMR signals of skeletal muscle and fat tissue in vivo: Two lipid compartments in muscle tissue. Magn Reson Med1993:29:158-167.
35. Boesch C, Slotboom J, Hoppeler H, Kreis R. In vivo determination of intra-myocellular lipids in human muscle by means of localized 1H-MR spectroscopy. Magn Reson Med 1997:37:484-493.
36. Boesch C, Kreis R. Observation of intramyocellular lipids by 1H-magnetic resonance spectroscopy. Ann N Y Acad Sci 2000:904:25-31.
37. Narayana PA, Jackson EF, Hazle JD, Fotedar LK, Kulkarni MV, Flamig DP. In vivo localized proton spectroscopic studies of human gastrocnemius muscle. Magn Reson Med 1988:8:151-159.
38. Bruhn H, Frahm J, Gyngell ML, Merboldt KD, Haenicke W, Sauter R. Localized proton NMR spectroscopy using stimulated echoes: Applications to human skeletal muscle in vivo. Magn Reson Med 1991:17:82-94.
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.
40. Thomas MA, Narayan P, Kurhanewicz J, Jajodia P, Weiner MW. 1H MR spectroscopy of normal and malignant human prostates in vivo. J Magn Reson 1990:87:610-619.
41. Schick F, Bongers H, Kurz S, Jung WI, Pfeffer M, Lutz O, Claussen CD. Localized proton MR spectroscopy of citrate in vitro and of human prostate in vivo at 1.5 T. Magn Reson Med 1992:29:38-43.
42. Kurhanewicz J, Vigneron DB, Hricak H, Narayan P, Carroll P, Nelson SJ. Three-dimensional H-1 MR spectroscopic imaging of the in situ human prostate with high (0.24 - 0.7-cm3) spatial resolution. Radiology1996:198:795-805.
43. Dixon RM, Frahm J. Localized proton MR spectroscopy of the human kidney in vivo by means of short echo time STEAM sequences. Magn Reson Med 1994:31:482-487.
44. Connelly A, Jackson GD, Duncan JS, King MD, Gadian DG. Magnetic resonance spectroscopy in temporal lobe epilepsy. Neurology 1994:44:1411-1417.
45. Ranjeva JP, Confort-Gouny S, Le Fur Y, Cozzone PJ. Magnetic resonance spectroscopy of brain in epilepsy.
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46. Chu WJ, Kuzniecky RI, Hugg JW, Abou-Khalil B, Gilliam F, Faught E, Hetherington HP. Statistically driven identification of focal metabolic abnormalities in temporal lobe epilepsy with corrections for tissueheterogeneity using 1H spectroscopic imaging. Magn Reson Med 2000:43:359-367.
47. Li LM, Cendes F, Antel SB, Andermann F, Serles W, Dubeau F, Olivier A, Arnold DL. Prognostic value of proton magnetic resonance spectroscopic imaging for surgical outcome in patients with intractable temporallobe epilepsy and bilateral hippocampal atrophy. Ann Neurol 2000:47:195-200.
48. Kuzniecky R, Hugg J, Hetherington H, Martin R, Faught E, Morawetz R, Gilliam F. Predictive value of 1H MRSI for outcome in temporal lobectomy. Neurology 1999:53:694-698.
49. Shonk TK, Moats RA, Gifford P, Michaelis T, Mandigo JC, Izumi J, Ross BD. Probable Alzheimer disease: Diagnosis with proton MR spectroscopy. Radiology 1995:195:65-72.
50. Michaelis T, Videen JS, Linsey MS, Ross BD. Dialysis and transplantation affect cerebral abnormalities of end-stage renal disease. J Magn Reson Imag 1996:6:341-347.
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 encephalopathy detected with H-1 MR spectroscopy. Radiology 1992:182:19-27.
53. Gideon P, Sperling B, Arlien-S¢borg P, Olsen TS, Henriksen O. Long-term follow-up of cerebral infarction patients with proton magnetic resonance spectroscopy. Stroke 1994:25:967-973.
54. Graham GD, Kalvach P, Blamire AM, Brass LM, Fayad PB, Prichard JW. Clinical correlates of proton magnetic resonance spectroscopy findings after acute cerebral infarction. Stroke 1995:26:225-229.
55. Gillard JH, Barker PB, van Zijl PCM, Bryan RN, Oppenheimer SM. Proton MR spectroscopy in acute middle cerebral artery stroke. AJNR 1996:17:873-886.
56. Pereira AC, Saunders DE, Doyle VL, Bland JM, Howe FA, Griffiths JR, Brown MM. Measurement of initial N-acetyl aspartate concentration by magnetic resonance spectroscopy and initial infarct volume by MRIpredicts outcome in patients with middle cerebral artery territory infarction. Stroke 1999:30:1577-1582.
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61. Poptani H, Kaartinen J, Gupta RK, Niemitz M, Hiltunen Y, Kauppinen RA. Diagnostic assessment of brain tumours and non-neoplastic brain disorders in vivo using proton nuclear magnetic resonance spectroscopyand artificial neural networks. J Cancer Res Clin Oncol 1999:125:343-349.
62. Preul MC, Caramanos Z, Villemure JG, Shenouda G, Leblanc R, Langleben A, Arnold DL. Using proton magnetic resonance spectroscopic imaging to predict in vivo the response of recurrent malignant gliomas totamoxifen chemotherapy. Neurosurgery 2000:46:306-318.
63. Maxwell RJ, Martinez-Perez I, Cerdan S, Cabanas ME, Arus C, Moreno A, Capdevila A, Ferrer E, Bartomeus F, Aparicio A, and others. Pattern recognition analysis of 1H NMR spectra from perchloric acidextracts of human brain tumor biopsies. Magn Reson Med 1998:39:869-877.
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65. Tate AR, Griffiths JR, Martinez-Perez I, Moreno A, Barba I, Cabanas ME, Watson D, Alonso J, Bartumeus F, Isamat F, and others. Towards a method for automated classification of 1H MRS spectra from braintumours. NMR Biomed 1998:11:177-191.
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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 87. Kreis R, Arcinue E, Ernst T, Shonk TK, Flores R, Ross BD. Hypoxic encephalopathy after near-drowning 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"

Source: http://www.amsm.dkf.unibe.ch/1-HMRSsyll.pdf