Skip to main content
SpringerLink
Log in

Differential kinetics of α-[11C]methyl-l-tryptophan on PET in low-grade brain tumors

  • Clinical Study – Patient Study
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Increased tryptophan metabolism via the kynurenine pathway is a major mechanism of tumor immuno-resistance. α-[11C]Methyl-l-tryptophan (AMT) is a positron emission tomography (PET) tracer for tryptophan catabolism, and increased AMT uptake has been demonstrated in brain tumors. In this study we evaluated the use of AMT PET for detection of low-grade gliomas and glioneuronal tumors, and determined if kinetic parameters of AMT uptake can differentiate among tumor types. AMT PET images were obtained in 23 patients with newly diagnosed low-grade brain tumors (WHO grade II gliomas and WHO grade I dysembryoplastic neuroepithelial tumors [DNETs]). Kinetic variables, including the unidirectional uptake rate (K-complex) and volume of distribution (VD; which characterizes tracer transport), were measured using a graphical approach from tumor dynamic PET and blood-input data, and metabolic rates (\( k^{\prime}_{3} \)) were also calculated. These values as well as tumor/cortex ratios were compared across tumor types. AMT PET showed increased tumor/cortex K-complex (n = 16) and/or VD ratios (n = 15) in 21/23 patients (91%), including 11/13 tumors with no gadolinium enhancement on MRI. No increases in AMT were seen in an oligodendroglioma and a DNET. Astrocytomas and oligoastrocytomas showed higher \( k^{\prime}_{3} \) tumor/cortex ratios (1.66 ± 0.46) than oligodendrogliomas (0.96 ± 0.21; P = 0.001) and DNETs (0.75 ± 0.39; P < 0.001). These results demonstrate that AMT PET identifies most low-grade gliomas and DNETs by high uptake, even if these tumors are not contrast-enhancing on MRI. Kinetic analysis of AMT uptake shows significantly higher tumor/cortex tryptophan metabolic ratios in astrocytomas and oligoastrocytomas in comparison with oligodendrogliomas and DNETs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Diksic M, Nagahiro S, Sourkes TL, Yamamoto YL (1990) A new method to measure brain serotonin synthesis in vivo. I. Theory and basic data for a biological model. J Cereb Blood Flow Metab 10:1–12

    Article  PubMed  CAS  Google Scholar 

  2. Muzik O, Chugani DC, Chakraborty P, Mangner T, Chugani HT (1997) Analysis of [C-11]alpha-methyl-tryptophan kinetics for the estimation of serotonin synthesis rate in vivo. J Cereb Blood Flow Metab 17:659–669

    Article  PubMed  CAS  Google Scholar 

  3. Chugani DC, Muzik O (2000) Alpha[C-11]methyl-l-tryptophan PET maps brain serotonin synthesis and kynurenine pathway metabolism. J Cereb Blood Flow Metab 20:2–9

    Article  PubMed  CAS  Google Scholar 

  4. Munn DH, Mellor AL (2007) Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J Clin Invest 117:1147–1154

    Article  PubMed  CAS  Google Scholar 

  5. Batista CEA, Juhász C, Muzik O, Kupsky WJ, Barger G, Chugani HT, Chugani HT, Mittal S, Sood S, Chakraborty PK, Chugani DC (2009) Imaging correlates of differential expression of indoleamine 2,3-dioxygenase in human brain tumors. Mol Imaging Biol 11:460–466

    Article  PubMed  Google Scholar 

  6. Chen W (2007) Clinical applications of PET in brain tumors. J Nucl Med 48:1468–1481

    Article  PubMed  Google Scholar 

  7. Mittal S, Szlaczky MC, Barger GR (2008) Low-grade gliomas in adults. Curr Treat Options Neurol 10:271–284

    Article  PubMed  Google Scholar 

  8. Juhász C, Chugani DC, Muzik O et al (2006) In vivo uptake and metabolism of alpha-[11C]methyl-l-tryptophan in human brain tumors. J Cereb Blood Flow Metab 26:345–357

    Article  PubMed  Google Scholar 

  9. Atkinson M, Juhász C, Shah J, Guo X, Kupsky W, Fuerst D, Johnson R, Watson C (2008) Paradoxical imaging findings in cerebral gliomas. J Neurol Sci 269:180–183

    Article  PubMed  Google Scholar 

  10. Chugani DC, Muzik O, Chakraborty P, Mangner T, Chugani HT (1998) Human brain serotonin synthesis capacity measured in vivo with alpha-[C-11]methyl-l-tryptophan. Synapse 28:33–43

    Article  PubMed  CAS  Google Scholar 

  11. Muzik O, Behrendt DB, Mangner TJ, Chugani HT (1994) Design of a pediatric protocol for quantitative brain FDG studies with PET not requiring invasive blood sampling. J Nucl Med 35:104 [abstract]

    Google Scholar 

  12. Suhonen-Pulvi H, Ruotsalainen U, Kinnala A, Bergman J, Haaparanta M, Teräs M, Mäkelä P, Solin O, Wegelius U (1995) FDG-PET in early infancy: simplified quantification methods to measure cerebral glucose utilization. J Nucl Med 36:1249–1254

    Google Scholar 

  13. Gjedde A (1981) High- and low-affinity transport of d-glucose from blood to brain. J Neurochem 36:1463–1471

    Article  PubMed  CAS  Google Scholar 

  14. Patlak CS, Blasberg RG, Fenstermacher JD (1983) Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. J Cereb Blood Flow Metab 3:1–7

    Article  PubMed  CAS  Google Scholar 

  15. Juhász C, Chugani DC, Muzik O, Shah A, Asano E, Mangner T, Chakraborty PK, Sood S, Chugani HT (2003) Alpha-methyl-l-tryptophan PET detects epileptogenic cortex in children with intractable epilepsy. Neurology 60:960–968

    PubMed  Google Scholar 

  16. Pollack IF (1994) Brain tumors in children. N Engl J Med 331:1500–1507

    Article  PubMed  CAS  Google Scholar 

  17. Schomas DA, Laack NN, Rao RD, Meyer FB, Shaw EG, O’Neill BP, Giannini C, Brown PD (2009) Intracranial low-grade gliomas in adults: 30-year experience with long-term follow-up at Mayo Clinic. Neuro-Oncology 11:437–445

    Article  PubMed  Google Scholar 

  18. Vertosick FT Jr, Selker RG, Arena VC (1991) Survival of patients with well-differentiated astrocytomas diagnosed in the era of computed tomography. Neurosurgery 28:496–501

    Article  PubMed  Google Scholar 

  19. McCormack BM, Miller DC, Budzilovich GN, Voorhees GJ, Ransohoff J (1992) Treatment and survival of low-grade astrocytoma in adults—1977–1988. Neurosurgery 31:636–642

    Article  PubMed  CAS  Google Scholar 

  20. Mason WP, Krol GS, DeAngelis LM (1996) Low-grade oligodendroglioma responds to chemotherapy. Neurology 46:203–207

    PubMed  CAS  Google Scholar 

  21. Olson JD, Riedel E, DeAngelis LM (2000) Long-term outcome of low-grade oligodendroglioma and mixed glioma. Neurology 54:1442–1448

    PubMed  CAS  Google Scholar 

  22. Kitange GJ, Smith JS, Jenkins RB (2001) Genetic alterations and chemotherapeutic response in human diffuse gliomas. Expert Rev Anticancer Ther 1:595–605

    Article  PubMed  CAS  Google Scholar 

  23. Tozer DJ, Jäger HR, Danchaivijitr N, Benton CE, Tofts PS, Rees JH, Waldman AD (2007) Apparent diffusion coefficient histograms may predict low-grade glioma subtype. NMR Biomed 20:49–57

    Article  PubMed  Google Scholar 

  24. Khayal IS, McKnight TR, McGue C, Vandenberg S, Lamborn KR, Chang SM, Cha S, Nelson SJ (2009) Apparent diffusion coefficient and fractional anisotropy of newly diagnosed grade II gliomas. NMR Biomed 22:449–455

    Article  PubMed  Google Scholar 

  25. Khayal IS, Nelson SJ (2009) Characterization of low-grade gliomas using RGB color maps derived from ADC histograms. J Magn Reson Imaging 30:209–213

    Article  PubMed  Google Scholar 

  26. Galldiks N, Kracht LW, Berthold F, Miletic H, Klein JC, Herholz K, Jacobs AH, Heiss WD (2010) [11C]-l-Methionine positron emission tomography in the management of children and young adults with brain tumors. J Neurooncol 96:231–239

    Article  PubMed  Google Scholar 

  27. Hatakeyama T, Kawai N, Nishiyama Y, Yamamoto Y, Sasakawa Y, Ichikawa T, Tamiya T (2008) 11C-Methionine (MET) and 18F-fluorothymidine (FLT) PET in patients with newly diagnosed glioma. Eur J Nucl Med Mol Imaging 35:2009–2017

    Article  PubMed  CAS  Google Scholar 

  28. Kato T, Shinoda J, Nakayama N, Miwa K, Okumura A, Yano H, Yoshimura S, Maruyama T, Muragaki Y, Iwama T (2008) Metabolic assessment of gliomas using 11C-methionine, [18F] fluorodeoxyglucose, and 11C-choline positron-emission tomography. AJNR Am J Neuroradiol 29:1176–1182

    Article  PubMed  CAS  Google Scholar 

  29. Kato T, Shinoda J, Oka N, Miwa K, Nakayama N, Yano H, Maruyama T, Muragaki Y, Iwama T (2008) Analysis of 11C-methionine uptake in low-grade gliomas and correlation with proliferative activity. AJNR Am J Neuroradiol 29:1867–1871

    Article  PubMed  CAS  Google Scholar 

  30. Maehara T, Nariai T, Arai N, Kawai K, Shimizu H, Ishii K, Ishiwata K, Ohno K (2004) Usefulness of [11C]methionine PET in the diagnosis of dysembryoplastic neuroepithelial tumor with temporal lobe epilepsy. Epilepsia 45:41–45

    Article  PubMed  Google Scholar 

  31. Rosenberg DS, Demarquay G, Jouvet A, Le Bars D, Streichenberger N, Sindou M, Kopp N, Mauguière F, Ryvlin P (2005) [11C]-Methionine PET: dysembryoplastic neuroepithelial tumours compared with other epileptogenic brain neoplasms. J Neurol Neurosurg Psychiatry 76:1686–1692

    Article  PubMed  CAS  Google Scholar 

  32. Okubo S, Zhen HN, Kawai N, Nishiyama Y, Haba R, Tamiya T (2010) Correlation of l-methyl-11C-methionine (MET) uptake with l-type amino acid transporter 1 in human gliomas. J Neurooncol. doi:10.1007/s11060-010-0117-9

  33. Astigiano S, Morandi B, Costa R, Mastracci L, D’Agostino A, Ratto GB, Melioli G, Frumento G (2005) Eosinophil granulocytes account for indoleamine 2,3-dioxygenase-mediated immune escape in human non-small cell lung cancer. Neoplasia 7:390–396

    Article  PubMed  CAS  Google Scholar 

  34. Okamoto A, Nikaido T, Ochiai K, Takakura S, Saito M, Aoki Y, Ishii N, Yanaihara N, Yamada K, Takikawa O, Kawaguchi R, Isonishi S, Tanaka T, Urashima M (2005) Indoleamine 2,3-dioxygenase serves as a marker of poor prognosis in gene expression profiles of serous ovarian cancer cells. Clin Cancer Res 11:6030–6039

    Article  PubMed  CAS  Google Scholar 

  35. Brandacher G, Perathoner A, Ladurner R, Schneeberger S, Obrist P, Winkler C, Werner ER, Werner-Felmayer G, Weiss HG, Göbel G, Margreiter R, Königsrainer A, Fuchs D, Amberger A (2006) Prognostic value of indoleamine 2,3-dioxygenase expression in colorectal cancer: effect on tumor-infiltrating T cells. Clin Cancer Res 12:1144–1151

    Article  PubMed  CAS  Google Scholar 

  36. Liu X, Newton RC, Friedman SM, Scherle PA (2009) Indoleamine 2,3-dioxygenase, an emerging target for anti-cancer therapy. Curr Cancer Drug Targets 9:938–952

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The study was supported by a grant from the National Cancer Institute (#CA123451, to C. Juhász). The authors thank Cathie Germain, MA, Angela Wigeluk, CNMT, Carole Clapko, CNMT, Galina Rabkin, CNMT, Melissa Burkett, CNMT, Andrew Mosqueda, CNMT, Anna DeBoard, RN, Jane Cornett, RN, and Mei-li Lee, MS, for their assistance in patient recruitment and preparation, as well as performing the PET studies.

Author information

Authors and Affiliations

  1. PET Center, Children’s Hospital of Michigan, Wayne State University School of Medicine, 3901 Beaubien Blvd., Detroit, MI, 48201, USA

    Csaba Juhász, Otto Muzik, Diane C. Chugani, Harry T. Chugani & Pulak K. Chakraborty

  2. Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA

    Csaba Juhász, Otto Muzik, Diane C. Chugani, Harry T. Chugani & Sandeep Sood

  3. Department of Neurology, Wayne State University School of Medicine, Detroit, MI, USA

    Csaba Juhász, Otto Muzik, Harry T. Chugani & Geoffrey R. Barger

  4. Department of Radiology, Wayne State University School of Medicine, Detroit, MI, USA

    Otto Muzik, Diane C. Chugani & Pulak K. Chakraborty

  5. Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, USA

    Sandeep Sood & Sandeep Mittal

  6. The Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA

    Csaba Juhász, Geoffrey R. Barger & Sandeep Mittal

Authors
  1. Csaba Juhász
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Otto Muzik
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Diane C. Chugani
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Harry T. Chugani
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sandeep Sood
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Pulak K. Chakraborty
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Geoffrey R. Barger
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Sandeep Mittal
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Csaba Juhász.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Juhász, C., Muzik, O., Chugani, D.C. et al. Differential kinetics of α-[11C]methyl-l-tryptophan on PET in low-grade brain tumors. J Neurooncol 102, 409–415 (2011). https://doi.org/10.1007/s11060-010-0327-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-010-0327-1

Keywords

Search

Navigation