Brain regional α-[11C]methyl-L-tryptophan trapping, used as an index of 5-HT synthesis, in healthy adults: absence of an age effect

  • Pedro Rosa-Neto
  • Chawki Benkelfat
  • Yojiro Sakai
  • Marco Leyton
  • Jose A. Morais
  • Mirko Diksic
Original Article

Abstract

Purpose

Previous functional neuroimaging studies suggest that selective aspects of the brain serotonin (5-HT) system change during the aging process. Here, we assessed the effects of aging on the brain regional α-[11C]methyl-L-tryptophan (α-[11C]MTrp) trapping rate constant (K*; μl·g−1·min−1), which, with certain assumptions, could be taken as a proxy of 5-HT synthesis.

Methods

Thirty-six healthy right-handed subjects had positron emission tomography (PET) scans following injection with α-[11C]MTrp [18 males aged 46.6 ± 22.2 years (range 20–80 years) and 18 females aged 33.0 ± 15.5 years (range 20–80 years)]. The trapping rate constant, K*, was calculated with the graphical method for irreversible ligands using the sinus-venous input function. A priori selected volumes of interest (VOIs) were defined using an automatic algorithm.

Results

VOI analysis showed no correlation between age and brain regional K* values. As reported by others, significant age-related reductions of gray matter were observed in the thalamus and frontal and cingulate cortices; even with partial volume correction there was still no significant relationship between K* and age. Further exploratory SPM voxelwise correlation between age and α-[11C]MTrp trapping, using p = 0.05 (uncorrected), as well as voxel-based morphometry, was in agreement with the VOI analysis.

Conclusion

The dissociation between age-related changes in brain anatomy and this index of serotonin synthesis suggests independent mechanisms underlying the normal aging process.

Keywords

Positron emission tomography 5-HT α-MTrp brain trapping Serotonin synthesis Brain morphometry Voxel-based morphometry 

Notes

Acknowledgements

The research was supported in part by grants from the NIH, CIHR, and FRSQ. We would like to acknowledge the dedicated technical support from the Radiochemistry-Cyclotron and Positron Emission Tomography Units. M.D. is a Killam Scholar at the Montreal Neurological Institute, McGill University, C.B. holds a Chercheur National Award and M.L. holds a Chercheur Boursier from FRSQ. In addition, we would like to thank S. Milot and S.N. Young for their help and suggestions during this study.

References

  1. 1.
    Machado A, Cano J, Santiago M. The change with age in biogenic amines and their metabolites in the striatum of the rat. Arch Gerontol Geriatr 1986;5:333–42.CrossRefPubMedGoogle Scholar
  2. 2.
    Frazer A, Hensler J, Serotonin. In: Siegel G, Agranoff B, Albers R, Fisher S, Uhler M, eds. Basic neurochemistry, molecular, cellular, and medical sspects. 6th ed. Philadelphia: Lippincott, Williams & Wilkins, 1999.Google Scholar
  3. 3.
    Costes N, Merlet I, Ostrowsky K, Faillenot I, Lavenne F, Zimmer L, et al. A 18F-MPPF PET normative database of 5-HT1A receptor binding in men and women over aging. J Nucl Med 2005;46:1980–9.PubMedGoogle Scholar
  4. 4.
    Meltzer CC, Reynolds CF 3rd. In vivo assessment of aging changes in serotonin function. Neuropsychopharmacology 1999;21:323–4.CrossRefPubMedGoogle Scholar
  5. 5.
    Tauscher J, Verhoeff NP, Christensen BK, Hussey D, Meyer JH, Kecojevic A, et al. Serotonin 5-HT1A receptor binding potential declines with age as measured by [11C]WAY-100635 and PET. Neuropsychopharmacology 2001;24:522–30.CrossRefPubMedGoogle Scholar
  6. 6.
    Wong DF, Wagner HN Jr, Dannals RF, Links JM, Frost JJ, Ravert HT, et al. Effects of age on dopamine and serotonin receptors measured by positron tomography in the living human brain. Science 1984;226:1393–6.CrossRefPubMedGoogle Scholar
  7. 7.
    Adams KH, Pinborg LH, Svarer C, Hasselbalch SG, Holm S, Haugbol S, et al. A database of [18F]-altanserin binding to 5-HT2A receptors in normal volunteers: normative data and relationship to physiological and demographic variables. Neuroimage 2004;21:1105–13.CrossRefPubMedGoogle Scholar
  8. 8.
    Meltzer CC, Drevets WC, Price JC, Mathis CA, Lopresti B, Greer PJ, et al. Gender-specific aging effects on the serotonin 1A receptor. Brain Res 2001;895:9–17.CrossRefGoogle Scholar
  9. 9.
    Rabiner EA, Messa C, Sargent PA, Husted-Kjaer K, Montgomery A, Lawrence AD, et al. A database of [11C]WAY-100635 binding to 5-HT1A receptors in normal male volunteers: normative data and relationship to methodological, demographic, physiological, and behavioral variables. Neuroimage 2002;15:620–32.CrossRefPubMedGoogle Scholar
  10. 10.
    Sheline YI, Mintun MA, Moerlein SM, Snyder AZ. Greater loss of 5-HT2A receptors in midlife than in late life. Am J Psychiatry 2002;159:430–5.CrossRefPubMedGoogle Scholar
  11. 11.
    Yamamoto M, Suhara T, Okubo Y, Ichimiya T, Sudo Y, Inoue M, et al. Age-related decline of serotonin transporters in living human brain of healthy males. Life Sci 2002;71:751–7.CrossRefPubMedGoogle Scholar
  12. 12.
    Goldberg S, Smith GS, Barnes A, Ma Y, Kramer E, Robeson K, et al. Serotonin modulation of cerebral glucose metabolism in normal aging. Neurobiol Aging 2004;25:167–74.CrossRefPubMedGoogle Scholar
  13. 13.
    Hagberg GE, Torstenson R, Marteinsdottir I, Fredrikson M, Langstrom B, Blomqvist G. Kinetic compartment modeling of [11C]-5-hydroxy-L-tryptophan for positron emission tomography assessment of serotonin synthesis in human brain. J Cereb Blood Flow Metab 2002;22:1352–66.CrossRefPubMedGoogle Scholar
  14. 14.
    Diksic M, Tohyama Y, Takada A. Brain net unidirectional uptake of alpha-[14C]methyl-L-tryptophan (alpha-MTrp) and its correlation with regional serotonin synthesis, tryptophan incorporation into proteins, and permeability surface area products of tryptophan and alpha-MTrp. Neurochem Res 2000;25:1537–46.CrossRefPubMedGoogle Scholar
  15. 15.
    Nishizawa S, Benkelfat C, Young SN, Leyton M, Mzengeza S, de Montigny C, et al. Differences between males and females in rates of serotonin synthesis in human brain. Proc Natl Acad Sci USA 1997;94:5308–13.CrossRefPubMedGoogle Scholar
  16. 16.
    Diksic M, Young SN. Study of the brain serotonergic system with labeled alpha-methyl-L-tryptophan. J Neurochem 2001;78:1185–200.CrossRefPubMedGoogle Scholar
  17. 17.
    Cohen Z, Tsuiki K, Takada A, Beaudet A, Diksic M, Hamel E. In vivo-synthesized radioactively labelled alpha-methyl serotonin as a selective tracer for visualization of brain serotonin neurons. Synapse 1995;21:21–8.CrossRefPubMedGoogle Scholar
  18. 18.
    Gharib A, Balende C, Sarda N, Weissmann D, Plenevaux A, Luxen A, et al. Biochemical and autoradiographic measurements of brain serotonin synthesis rate in the freely moving rat: a reexamination of the alpha-methyl-L-tryptophan method. J Neurochem 1999;72:2593–600.CrossRefPubMedGoogle Scholar
  19. 19.
    Rosa-Neto P, Diksic M, Leyton M, Mzengeza S, Benkelfat C. Stability of alpha-[11C]methyl-L-tryptophan brain trapping in healthy male volunteers. Eur J Nucl Med Mol Imaging 2005;32:1199–204.CrossRefPubMedGoogle Scholar
  20. 20.
    Chugani DC, Niimura K, Chaturvedi S, Muzik O, Fakhouri M, Lee ML, et al. Increased brain serotonin synthesis in migraine. Neurology 1999;53:1473–9.PubMedGoogle Scholar
  21. 21.
    Natsume J, Kumakura Y, Bernasconi N, Soucy JP, Nakai A, Rosa P, et al. Alpha-[11C] methyl-L-tryptophan and glucose metabolism in patients with temporal lobe epilepsy. Neurology 2003;60:756–61.PubMedGoogle Scholar
  22. 22.
    Juhasz C, Chugani DC, Padhye UN, Muzik O, Shah A, Asano E, et al. Evaluation with alpha-[11C]methyl-L-tryptophan positron emission tomography for reoperation after failed epilepsy surgery. Epilepsia 2004;45:124–30.CrossRefPubMedGoogle Scholar
  23. 23.
    Chugani DC, Muzik O, Behen M, Rothermel R, Janisse JJ, Lee J, et al. Developmental changes in brain serotonin synthesis capacity in autistic and nonautistic children. Ann Neurol 1999;45:287–95.CrossRefPubMedGoogle Scholar
  24. 24.
    Leyton M, Okazawa H, Diksic M, Paris J, Rosa P, Mzengeza S, et al. Brain Regional alpha-[11C]methyl-L-tryptophan trapping in impulsive subjects with borderline personality disorder. Am J Psychiatry 2001;158:775–82.CrossRefPubMedGoogle Scholar
  25. 25.
    Rosa-Neto P, Diksic M, Okazawa H, Leyton M, Ghadirian N, Mzengeza S, et al. Measurement of brain regional alpha-[11C]methyl-L-tryptophan trapping as a measure of serotonin synthesis in medication-free patients with major depression. Arch Gen Psychiatry 2004;61:556–63.CrossRefPubMedGoogle Scholar
  26. 26.
    Leyton M, Paquette V, Gravel P, Rosa-Neto P, Weston F, Diksic M, et al. alpha-[11C]Methyl-L-tryptophan trapping in the orbital and ventral medial prefrontal cortex of suicide attempters. Eur Neuropsychopharmacol 2006;16:220–3.CrossRefPubMedGoogle Scholar
  27. 27.
    Juhasz C, Chugani DC, Muzik O, Wu D, Sloan AE, Barger G, et al. In vivo uptake and metabolism of alpha-[11C]methyl-L-tryptophan in human brain tumors. J Cereb Blood Flow Metab 2006;26:345–57.CrossRefPubMedGoogle Scholar
  28. 28.
    Shoaf SE, Carson RE, Hommer D, Williams WA, Higley JD, Schmall B, et al. The suitability of [11C]-alpha-methyl-L-tryptophan as a tracer for serotonin synthesis: studies with dual administration of [11C] and [14C] labeled tracer. J Cereb Blood Flow Metab 2000;20:244–52.CrossRefPubMedGoogle Scholar
  29. 29.
    Nishikawa M, Kumakura Y, Young SN, Fiset P, Vogelzangs N, Leyton M, et al. Increasing blood oxygen increases an index of 5-HT synthesis in human brain as measured using alpha-[11C]methyl-L-tryptophan and positron emission tomography. Neurochem Int 2005;47:556–64.CrossRefPubMedGoogle Scholar
  30. 30.
    Goldman-Rakic PS, Brown RM. Regional changes of monoamines in cerebral cortex and subcortical structures of aging rhesus monkeys. Neuroscience 1981;6:177–87.CrossRefPubMedGoogle Scholar
  31. 31.
    Miguez JM, Aldegunde M, Paz-Valinas L, Recio J, Sanchez-Barcelo E. Selective changes in the contents of noradrenaline, dopamine and serotonin in rat brain areas during aging. J Neural Transm 1999;106:1089–98.CrossRefPubMedGoogle Scholar
  32. 32.
    Moretti A, Carfagna N, Trunzo F. Effect of aging on monoamines and their metabolites in the rat brain. Neurochem Res 1987;12:1035–9.CrossRefPubMedGoogle Scholar
  33. 33.
    Ponzio F, Calderini G, Lomuscio G, Vantini G, Toffano G, Algeri S. Changes in monoamines and their metabolite levels in some brain regions of aged rats. Neurobiol Aging 1982;3:23–9.CrossRefPubMedGoogle Scholar
  34. 34.
    Hussain AM, Mitra AK. Effect of reactive oxygen species on the metabolism of tryptophan in rat brain: influence of age. Mol Cellul Biochem 2004;258:145–53.CrossRefGoogle Scholar
  35. 35.
    Hesse S, Barthel H, Murai T, Muller U, Muller D, Seese A, et al. Is correction for age necessary in neuroimaging studies of the central serotonin transporter? Eur J Nucl Med Mol Imaging 2003;30:427–30.PubMedCrossRefGoogle Scholar
  36. 36.
    Pirker W, Asenbaum S, Hauk M, Kandlhofer S, Tauscher J, Willeit M, et al. Imaging serotonin and dopamine transporters with 123I-beta-CIT SPECT: binding kinetics and effects of normal aging. J Nucl Med 2000;41:36–44.PubMedGoogle Scholar
  37. 37.
    First M, Spitzer R, Gibbon M, Williams J. Structured clinical interview for the DSM–IV Axis I disorders (SCID I/P, Version 2.0). New York: Biometrics Research Department, New York State Psychiatric Institute, 1995.Google Scholar
  38. 38.
    Beck A, Beamesdefer A. Assessment of depression: the depression inventory. In: Pickot P, ed. Modern problems in psychopharmachology. Basel: S. Karger, 1974.Google Scholar
  39. 39.
    Nurnberger JI Jr, Blehar MC, Kaufmann CA, York-Cooler C, Simpson SG, Harkavy-Friedman J, et al. Diagnostic interview for genetic studies. Rationale, unique features, and training. NIMH Genetics Initiative. Arch Gen Psychiatry 1994;51:849–59; discussion 863–4.PubMedGoogle Scholar
  40. 40.
    Nishizawa S, Leyton M, Okazawa H, Benkelfat C, Mzengeza S, Diksic M. Validation of a less-invasive method for measurement of serotonin synthesis rate with alpha-[11C]methyl-tryptophan. J Cereb Blood Flow Metab 1998;18:1121–9.CrossRefPubMedGoogle Scholar
  41. 41.
    Patlak CS, Blasberg RG, Fenstermacher JD. Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. J Cereb Blood Flow Metab 1983;3:1–7.PubMedGoogle Scholar
  42. 42.
    Okazawa H, Diksic M. Image generation of serotonin synthesis rates using alpha-methyltryptophan and PET. J Comput Assist Tomogr 1998;22:777–85.CrossRefPubMedGoogle Scholar
  43. 43.
    Collins D, Zijdenbos A, Barré W, Evans A. ANIMAL+INSECT: improved cortical structure segmentation. In: Kuba A SMaT-PA, ed. Proceedings of the Annual Symposium on Information Processing in Medical Imaging. Vol. 1613, 1999:210–23.Google Scholar
  44. 44.
    Sled JG, Zijdenbos AP, Evans AC. A nonparametric method for automatic correction of intensity nonuniformity in MRI data. IEEE Trans Med Imaging 1998;17:87–97.CrossRefPubMedGoogle Scholar
  45. 45.
    Zijdenbos A, Forghani R, Evans AC. Automatic quantification of MS lesions in 3D MRI brain data sets: validation of INSECT. Proceedings of the first International conference on medical image computing and computer-assisted intervention (MICCAI). Berlin: Springer, 1998.Google Scholar
  46. 46.
    Aston JA, Cunningham VJ, Asselin MC, Hammers A, Evans AC, Gunn RN. Positron emission tomography partial volume correction: estimation and algorithms. J Cereb Blood Flow Metab 2002;22:1019–34.CrossRefPubMedGoogle Scholar
  47. 47.
    Friston KJ. Commentary and opinion: II. Statistical parametric mapping: ontology and current issues. J Cereb Blood Flow Metab 1995;15:361–70.PubMedGoogle Scholar
  48. 48.
    Tisserand DJ, van Boxtel MP, Pruessner JC, Hofman P, Evans AC, Jolles J. A voxel-based morphometric study to determine individual differences in gray matter density associated with age and cognitive change over time. Cereb Cortex 2004;14:966–73.CrossRefPubMedGoogle Scholar
  49. 49.
    Ito H, Hatazawa J, Murakami M, Miura S, Iida H, Bloomfield PM, et al. Aging effect on neutral amino acid transport at the blood-brain barrier measured with L-[2-18F]-fluorophenylalanine and PET. J Nucl Med 1995;36:1232–7.PubMedGoogle Scholar
  50. 50.
    Koeppe RA, Shulkin BL, Rosenspire KC, Shaw LA, Betz AL, Mangner T, et al. Effect of aspartame-derived phenylalanine on neutral amino acid uptake in human brain: a positron emission tomography study. J Neurochem 1991;56:1526–35.CrossRefPubMedGoogle Scholar
  51. 51.
    Iyo M, Yamasaki T. The detection of age-related decrease of dopamine D1, D2 and serotonin 5-HT2 receptors in living human brain. Prog Neuropsychopharmacol Biol Psychiatry 1993;17:415–21.CrossRefPubMedGoogle Scholar
  52. 52.
    Meltzer CC, Smith G, Price JC, Reynolds CF III, Mathis CA, Greer P, et al. Reduced binding of [18F]altanserin to serotonin type 2A receptors in aging: persistence of effect after partial volume correction. Brain Res 1998;813:167–71.CrossRefPubMedGoogle Scholar
  53. 53.
    Parsey RV, Oquendo MA, Simpson NR, Ogden RT, Van Heertum R, Arango V, et al. Effects of sex, age, and aggressive traits in man on brain serotonin 5-HT1A receptor binding potential measured by PET using [C-11]WAY-100635. Brain Res 2002;954:173–82.CrossRefPubMedGoogle Scholar
  54. 54.
    Bjorklund A, Stenevi U. Intracerebral neural implants: neuronal replacement and reconstruction of damaged circuitries. Annu Rev Neurosci 1984;7:279–308.CrossRefPubMedGoogle Scholar
  55. 55.
    Kloppel S, Kovacs GG, Voigtlander T, Wanschitz J, Flicker H, Hainfellner JA, et al. Serotonergic nuclei of the raphe are not affected in human ageing. Neuroreport 2001;12:669–71.CrossRefPubMedGoogle Scholar
  56. 56.
    Fowler JS, Volkow ND, Wang GJ, Logan J, Pappas N, Shea C, et al. Age-related increases in brain monoamine oxidase B in living healthy human subjects. Neurobiol Aging 1997;18:431–5.CrossRefPubMedGoogle Scholar
  57. 57.
    Muzik O, Chugani DC, Chakraborty P, Mangner T, Chugani HT. Analysis of [C-11]alpha-methyl-tryptophan kinetics for the estimation of serotonin synthesis rate in vivo. J Cereb Blood Flow Metab 1997;17:659–69.CrossRefPubMedGoogle Scholar
  58. 58.
    Van Laere KJ, Dierckx RA. Brain perfusion SPECT: age-and sex-related effects correlated with voxel-based morphometric findings in healthy adults. Radiology 2001;221:810–7.CrossRefPubMedGoogle Scholar
  59. 59.
    Inoue K, Ito H, Goto R, Nakagawa M, Kinomura S, Sato T, et al. Apparent CBF decrease with normal aging due to partial volume effects: MR-based partial volume correction on CBF SPECT. Ann Nucl Med 2005;19:283–90.PubMedCrossRefGoogle Scholar
  60. 60.
    Good CD, Johnsrude IS, Ashburner J, Henson RN, Friston KJ, Frackowiak RS. A voxel-based morphometric study of ageing in 465 normal adult human brains. Neuroimage 2001;14:21–36.CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Pedro Rosa-Neto
    • 1
    • 2
  • Chawki Benkelfat
    • 1
    • 2
  • Yojiro Sakai
    • 1
    • 4
  • Marco Leyton
    • 1
    • 2
  • Jose A. Morais
    • 3
  • Mirko Diksic
    • 1
  1. 1.Department of Neurology and NeurosurgeryMontrealCanada
  2. 2.Department of PsychiatryMcGill UniversityMontrealCanada
  3. 3.Department of GeriatricsMcGill UniversityMontrealCanada
  4. 4.Department of Psychosomatic MedicineUniversity of TokyoTokyoJapan

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