Progression of dopamine transporter decline in patients with the Parkinson variant of multiple system atrophy: a voxel-based analysis of [123I]β-CIT SPECT

  • Michael Nocker
  • Klaus Seppi
  • Eveline Donnemiller
  • Irene Virgolini
  • Gregor K. Wenning
  • Werner Poewe
  • Christoph Scherfler
Original Article



We characterized the progression of dopamine transporter (DAT) decline in the striatum and extrastriatal regions including the midbrain and pons of patients with the Parkinson variant of multiple system atrophy (MSA-P) and compared longitudinally collected SPECT results with those in a cohort of patients with Parkinson's disease (PD).


Eight patients with MSA-P (age 60.4 ± 7.7 years, disease duration 2.4 ± 1 years, UPDRS-III motor score 39.7 ± 4.7), and 11 patients with PD (age 61.2 ± 6.4 years, disease duration 2.4 ± 1.1 years, UPDRS-III motor score 18.9 ± 7.6) underwent a baseline and follow-up [123I]β-CIT SPECT investigation within a time period of 1.3 years. Statistical parametric mapping (SPM) and a repetitive ANOVA design were used to objectively localize the decline in DAT availability without having to make an a priori hypothesis as to its location.


SPM localized significant reductions in [123I]β-CIT uptake in the dorsal brainstem of MSA-P patients compared to PD patients (p < 0.001) at baseline. Additional reductions in the DAT signal were localized in the caudate and anterior putamen of patients with MSA-P patients compared to PD patients at the follow-up examination (p < 0.001). Relative decline in tracer binding was evident in the caudate and anterior putamen of MSA-P patients compared to PD patients in the longitudinal analysis (p < 0.05), whereas no significant relative signal alteration was observed in the brainstem.


In contrast to PD, the relatively higher rate of signal reduction in the caudate and anterior putamen is consistent with the faster disease progression reported in MSA-P. At baseline, the tracer uptake in the brainstem was already at very low levels in the MSA-P patients compared to that in healthy control subjects and did not progress any further, suggesting that the degeneration of monoaminergic neurons is almost complete early in the disease course.


Multiple system atrophy Parkinson disease Dopamine transporter SPECT Voxel-by-voxel analysis 


  1. 1.
    Lantos PL. The definition of multiple system atrophy: a review of recent developments. J Neuropathol Exp Neurol. 1998;57:1099–111.PubMedCrossRefGoogle Scholar
  2. 2.
    Wenning GK, Tison F, Ben Shlomo Y, Daniel SE, Quinn NP. Multiple system atrophy: a review of 203 pathologically proven cases. Mov Disord. 1997;12:133–47.PubMedCrossRefGoogle Scholar
  3. 3.
    Wenning GK, Ben Shlomo Y, Magalhães M, Daniel SE, Quinn NP. Clinical features and natural history of multiple system atrophy. An analysis of 100 cases. Brain 1994;117(Pt 4):835–45.PubMedCrossRefGoogle Scholar
  4. 4.
    Watanabe H, Saito Y, Terao S, Ando T, Kachi T, Mukai E, et al. Progression and prognosis in multiple system atrophy: an analysis of 230 Japanese patients. Brain. 2002;125:1070–83.PubMedCrossRefGoogle Scholar
  5. 5.
    Ben-Shlomo Y, Wenning GK, Tison F, Quinn NP. Survival of patients with pathologically proven multiple system atrophy: a meta-analysis. Neurology. 1997;48:384–93.PubMedGoogle Scholar
  6. 6.
    Seibyl JP, Marek KL, Quinlan D, Sheff K, Zoghbi S, Zea-Ponce Y, et al. Decreased single-photon emission computed tomographic [123I]beta-CIT striatal uptake correlates with symptom severity in Parkinson's disease. Ann Neurol. 1995;38:589–98.PubMedCrossRefGoogle Scholar
  7. 7.
    Brucke T, Asenbaum S, Pirker W, Djamshidian S, Wenger S, Wober C, et al. Measurement of the dopaminergic degeneration in Parkinson's disease with [123I]beta-CIT and SPECT. Correlation with clinical findings and comparison with multiple system atrophy and progressive supranuclear palsy. J Neural Transm Suppl. 1997;50:9–24.PubMedGoogle Scholar
  8. 8.
    Marek K, Innis R, van Dyck C, Fussell B, Early M, Eberly S, et al. [123I]beta-CIT SPECT imaging assessment of the rate of Parkinson's disease progression. Neurology. 2001;57:2089–94.PubMedGoogle Scholar
  9. 9.
    Varrone A, Marek KL, Jennings D, Innis RB, Seibyl JP. [(123)I]beta-CIT SPECT imaging demonstrates reduced density of striatal dopamine transporters in Parkinson's disease and multiple system atrophy. Mov Disord. 2001;16:1023–32.PubMedCrossRefGoogle Scholar
  10. 10.
    Knudsen GM, Karlsborg M, Thomsen G, Krabbe K, Regeur L, Nygaard T, et al. Imaging of dopamine transporters and D2 receptors in patients with Parkinson's disease and multiple system atrophy. Eur J Nucl Med Mol Imaging. 2004;31:1631–8.PubMedCrossRefGoogle Scholar
  11. 11.
    Scherfler C, Seppi K, Donnemiller E, Goebel G, Brenneis C, Virgolini I, et al. Voxel-wise analysis of [123I]beta-CIT SPECT differentiates the Parkinson variant of multiple system atrophy from idiopathic Parkinson's disease. Brain. 2005;128:1605–12.PubMedCrossRefGoogle Scholar
  12. 12.
    Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality. Neurology. 1967;17:427–42.PubMedGoogle Scholar
  13. 13.
    Fahn S, Elton R. Unified Parkinson's disease rating scale. In: Fahn S, Marsden CD, Calne DB, Goldstein M, editors. Recent developments in Parkinson's disease. Vol. 2. Florham Park (NJ): Macmillan Health Care Information; 1987. p. 153–164.Google Scholar
  14. 14.
    Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry. 1992;55:181–4.PubMedCrossRefGoogle Scholar
  15. 15.
    Gilman S, Wenning GK, Low PA, Brooks DJ, Mathias CJ, Trojanowski JQ, et al. Second consensus statement on the diagnosis of multiple system atrophy. Neurology. 2008;71(9):670–6.PubMedCrossRefGoogle Scholar
  16. 16.
    Kuikka JT, Bergstrom KA, Ahonen A, Lansimies E. The dosimetry of iodine-123 labelled 2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane. Eur J Nucl Med. 1994;21:53–6.PubMedGoogle Scholar
  17. 17.
    Laruelle M, Wallace E, Seibyl JP, Baldwin RM, Zea-Ponce Y, Zoghbi SS, et al. Graphical, kinetic, and equilibrium analyses of in vivo [123I]beta-CIT binding to dopamine transporters in healthy human subjects. J Cereb Blood Flow Metab. 1994;14:982–94.PubMedCrossRefGoogle Scholar
  18. 18.
    Innis RB, Cunningham VJ, Delforge J, Fujita M, Gjedde A, Gunn RN, et al. Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab. 2007;27:1533–9.PubMedCrossRefGoogle Scholar
  19. 19.
    De Keyser J, De Backer JP, Ebinger G, Vauquelin G. [3H]GBR 12935 binding to dopamine uptake sites in the human brain. J Neurochem. 1989;53:1400–4.PubMedCrossRefGoogle Scholar
  20. 20.
    Rorden C, Brett M. Stereotaxic display of brain lesions. Behav Neurol. 2000;12:191–200.PubMedGoogle Scholar
  21. 21.
    Friston KJ, Ashburner J, Frith CD, Poline JB, Heather JD, Frackowiak RS. Spatial registration and normalization of images. Hum Brain Mapp. 1995;2:165–189.CrossRefGoogle Scholar
  22. 22.
    Rakshi JS, Uema T, Ito K, Bailey DL, Morrish PK, Ashburner J, et al. Frontal, midbrain and striatal dopaminergic function in early and advanced Parkinson's disease. A 3D [(18)F]dopa-PET study. Brain. 1999;122(Pt 9):1637–50.PubMedCrossRefGoogle Scholar
  23. 23.
    Worsley KJ, Marrett S, Neelin P, Vandal AC, Friston KJ, Evans AC. A unified statistical approach for determining significant signals in images of cerebral activation. Hum Brain Mapp. 1996;4:58–73.PubMedCrossRefGoogle Scholar
  24. 24.
    Antonini A, Benti R, De Notaris R, Tesei S, Zecchinelli A, Sacilotto G, et al. 123I-Ioflupane/SPECT binding to striatal dopamine transporter (DAT) uptake in patients with Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy. Neurol Sci. 2003;24:149–50.PubMedCrossRefGoogle Scholar
  25. 25.
    Pirker W, Djamshidian S, Asenbaum S, Gerschlager W, Tribl G, Hoffmann M, et al. Progression of dopaminergic degeneration in Parkinson's disease and atypical parkinsonism: a longitudinal beta-CIT SPECT study. Mov Disord. 2002;17:45–53.PubMedCrossRefGoogle Scholar
  26. 26.
    Scherfler C, Nocker M. Dopamine transporter SPECT: how to remove subjectivity? Mov Disord. 2009;24 Suppl 2:S721–4.PubMedCrossRefGoogle Scholar
  27. 27.
    Kim YJ, Ichise M, Ballinger JR, Vines D, Erami SS, Tatschida T, et al. Combination of dopamine transporter and D2 receptor SPECT in the diagnostic evaluation of PD, MSA, and PSP. Mov Disord. 2002;17:303–12.PubMedCrossRefGoogle Scholar
  28. 28.
    Brooks DJ, Salmon EP, Mathias CJ, Quinn N, Leenders KL, Bannister R, et al. The relationship between locomotor disability, autonomic dysfunction, and the integrity of the striatal dopaminergic system in patients with multiple system atrophy, pure autonomic failure, and Parkinson's disease, studied with PET. Brain. 1990;1990:1539–52.CrossRefGoogle Scholar
  29. 29.
    Kume A, Takahashi A, Hashizume Y. Neuronal cell loss of the striatonigral system in multiple system atrophy. J Neurol Sci. 1993;117:33–40.PubMedCrossRefGoogle Scholar
  30. 30.
    Morrish PK, Sawle GV, Brooks DJ. The rate of progression of Parkinson's disease. A longitudinal [18F]DOPA PET study. Adv Neurol. 1996;69:427–31.PubMedGoogle Scholar
  31. 31.
    Parkinson Study Group. Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression. JAMA. 2002;287(13):1653–61.CrossRefGoogle Scholar
  32. 32.
    Seibyl JP, Marek K, Sheff K, Baldwin RM, Zoghbi S, Zea-Ponce Y, et al. Test/retest reproducibility of iodine-123-betaCIT SPECT brain measurement of dopamine transporters in Parkinson's patients. J Nucl Med. 1997;38:1453–9.PubMedGoogle Scholar
  33. 33.
    Booij J, Habraken JB, Bergmans P, Tissingh G, Winogrodzka A, Wolters EC, et al. Imaging of dopamine transporters with iodine-123-FP-CIT SPECT in healthy controls and patients with Parkinson's disease. J Nucl Med. 1998;39:1879–84.PubMedGoogle Scholar
  34. 34.
    Morrish PK. How valid is dopamine transporter imaging as a surrogate marker in research trials in Parkinson’s disease. Mov Disord. 2003;18: Suppl 7:S63–70.PubMedCrossRefGoogle Scholar
  35. 35.
    Seppi K, Scherfler C, Donnemiller E, Virgolini I, Schocke MF, Goebel G, et al. Topography of dopamine transporter availability in progressive supranuclear palsy: a voxelwise [123I]beta-CIT SPECT analysis. Arch Neurol. 2006;63:1154–60.PubMedCrossRefGoogle Scholar
  36. 36.
    Innis R, Baldwin R, Sybirska E, Zea Y, Laruelle M, al-Tikriti M, et al. Single photon emission computed tomography imaging of monoamine reuptake sites in primate brain with [123I]CIT. Eur J Pharmacol. 1991;200:369–70.PubMedCrossRefGoogle Scholar
  37. 37.
    Staley JK, Basile M, Flynn DD, Mash DC. Visualizing dopamine and serotonin transporters in the human brain with the potent cocaine analogue [125I]RTI-55: in vitro binding and autoradiographic characterization. J Neurochem. 1994;62:549–56.PubMedCrossRefGoogle Scholar
  38. 38.
    Pirker W, Asenbaum S, Kasper S, Walter H, Angelberger P, Koch G, et al. beta-CIT SPECT demonstrates blockade of 5HT-uptake sites by citalopram in the human brain in vivo. J Neural Transm Gen Sect. 1995;100:247–56.PubMedCrossRefGoogle Scholar
  39. 39.
    Uhl GR. Neurotransmitter transporters (plus): a promising new gene family. Trends Neurosci. 1992;15:265–8.PubMedCrossRefGoogle Scholar
  40. 40.
    Wenning GK, Colosimo C, Geser F, Poewe W. Multiple system atrophy. Lancet Neurol. 2004;3:93–103.PubMedCrossRefGoogle Scholar
  41. 41.
    Papp MI, Lantos PL. The distribution of oligodendroglial inclusions in multiple system atrophy and its relevance to clinical symptomatology. Brain. 1994;117(Pt 2):235–43.PubMedCrossRefGoogle Scholar
  42. 42.
    Benarroch EE, Schmeichel AM, Low PA, Parisi JE. Involvement of medullary serotonergic groups in multiple system atrophy. Ann Neurol. 2004;55:418–22.PubMedCrossRefGoogle Scholar
  43. 43.
    Glover G, Pelc N. The nonlinear partial volume artefact. J Comput Assist Tomogr. 1979;25:79–86.Google Scholar
  44. 44.
    Hoffman EJ, Huang SC, Phelps ME. Quantification in positron emission tomography. 1. Effect of object size. J Comput Assist Tomogr. 1979;22:324–33.Google Scholar
  45. 45.
    Kojima A, Matsumoto M, Takahashi M, Hirota Y, Yoshida H. Effect of spatial resolution on SPECT quantification values. J Nucl Med. 1989;30:508–14.PubMedGoogle Scholar
  46. 46.
    Pirker W, Holler I, Gerschlager W, Asenbaum S, Zettinig G, Brucke T. Measuring the rate of progression of Parkinson's disease over a 5-year period with beta-CIT SPECT. Mov Disord. 2003;18:1266–72.PubMedCrossRefGoogle Scholar
  47. 47.
    Muller J, Wenning GK, Jellinger K, McKee A, Poewe W, Litvan I. Progression of Hoehn and Yahr stages in Parkinsonian disorders: a clinicopathologic study. Neurology. 2000;55:888–91.PubMedGoogle Scholar
  48. 48.
    Jankovic J, McDermott M, Carter J, Gauthier S, Goetz C, Golbe L, et al. Variable expression of Parkinson's disease: a base-line analysis of the DATATOP cohort. The Parkinson Study Group Neurology. 1990;40:1529–34.PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Michael Nocker
    • 1
  • Klaus Seppi
    • 1
  • Eveline Donnemiller
    • 2
  • Irene Virgolini
    • 2
  • Gregor K. Wenning
    • 1
  • Werner Poewe
    • 1
  • Christoph Scherfler
    • 1
  1. 1.Department of NeurologyInnsbruck Medical UniversityInnsbruckAustria
  2. 2.Department of Nuclear MedicineInnsbruck Medical UniversityInnsbruckAustria

Personalised recommendations