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Impaired brain dopamine transporter in chemobrain patients submitted to brain SPECT imaging using the technetium-99m labeled tracer TRODAT-1

  • Taise VitorEmail author
  • Elisa H. Kozasa
  • Rodrigo A. Bressan
  • Shirley S. Lacerda
  • Guilherme C. Campos Neto
  • Ilza Rosa Batista
  • Luiz Henrique Gebrim
  • Lorenzo Cohen
  • Edson Amaro
  • Andre C. Felicio
Original Article
  • 53 Downloads

Abstract

Purpose

“Chemobrain” is a medical secondary effect of cancer chemotherapy treatment characterized by a general decline in cognition affecting visual and verbal memory, attention, complex problem-solving skills, and motor function. Dopamine (DA) central nervous system neurotransmitters serve an important role in cognition, and changes in DA could potentially explain impaired cognition associated with chemotherapy. Therefore, our objective was to assess in vivo dopaminergic dysfunction in the central nervous system (CNS) of a group of female breast cancer survivors with cognitive impairment following chemotherapy.

Methods

Twenty-eight women reporting chemobrain were recruited for this study and compared to 22 healthy reference women. Striatal dopamine transporter (DAT) binding ratio was determined by 99mTc-TRODAT-1 (a highly selective radiotracer for DAT in the dorsal striatum) single-photon emission computed tomography and a quantitative evaluation was obtained by DatQUANT™ software (GE Healthcare). The DAT binding ratio (BRDAT) in the patient and control groups was compared using the Student’s t test, a multivariate analysis of variance (MANOVA) was used to compare age, years of schooling and BRDAT. The relationship between continuous variables, such as cognitive impairment and BRDAT was assessed using Pearson correlation test.

Results

There was a difference in BRDAT between the chemobrain patients and control group. Patients had statistically significant (p < 0.05) lower concentrations of the radiopharmaceutical in the striatum.

Conclusions

We identified a significant dopaminergic decrease in all regions of the dorsal striatum within the patients reporting cognitive dysfunction after chemotherapy. Therefore, our results indicate a possible role of dopamine transporter in the physiopathology of chemobrain, even out of the acute phase of symptoms.

Keywords

Dopamine transporter SPECT Chemobrain Chemotherapy TRODAT-1 

Notes

Acknowledgements

We are grateful to the Hospital Pérola Byington, Sāo Paulo, Brazil, and MD Anderson Cancer Center, Houston.

Funding

Hospital Israelita Albert Einstein.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent Informed consent was obtained from all individual participants or legitimate representatives included in the study.

Informed consent

Informed consent was obtained from all individual participants included in this study.

References

  1. 1.
    Koppelmans V, Vernooij MW, Boogerd W, Seynaeve C, Ikram MA, Breteler MM, et al. Prevalence of cerebral small-vessel disease in long-term breast cancer survivors exposed to both adjuvant radiotherapy and chemotherapy. J Clin Oncol. 2015;33(6):588–93.PubMedGoogle Scholar
  2. 2.
    Koppelmans V, de Groot M, de Ruiter MB, Boogerd W, Seynaeve C, Vernooij MW, et al. Global and focal white matter integrity in breast cancer survivors 20 years after adjuvant chemotherapy. Hum Brain Mapp. 2014;35(3):889–99.PubMedGoogle Scholar
  3. 3.
    Koppelmans V, Breteler MM, Boogerd W, Seynaeve C, Gundy C, Schagen SB. Neuropsychological performance in survivors of breast cancer more than 20 years after adjuvant chemotherapy. J Clin Oncol. 2012;30(10):1080–6.PubMedGoogle Scholar
  4. 4.
    Argyriou AA, Assimakopoulos K, Iconomou G, Giannakopoulou F, Kalofonos HP. Either called “chemobrain” or “chemofog,” the long-term chemotherapy-induced cognitive decline in cancer survivors is real. J Pain Symptom Manag. 2011;41(1):126–39.Google Scholar
  5. 5.
    Matsuda T, Takayama T, Tashiro M, Nakamura Y, Ohashi Y, Shimozuma K. Mild cognitive impairment after adjuvant chemotherapy in breast cancer patients—evaluation of appropriate research design and methodology to measure symptoms. Breast Cancer. 2005;12(4):279–87.PubMedGoogle Scholar
  6. 6.
    Jansen CE, Cooper BA, Dodd MJ, Miaskowski CA. A prospective longitudinal study of chemotherapy-induced cognitive changes in breast cancer patients. Support Care Cancer. 2011;19(10):1647–56.PubMedGoogle Scholar
  7. 7.
    Nelson CJ, Nandy N, Roth AJ. Chemotherapy and cognitive deficits: mechanisms, findings, and potential interventions. Palliat Support Care. 2007;5(3):273–80.PubMedGoogle Scholar
  8. 8.
    Boykoff N, Moieni M, Subramanian SK. Confronting chemobrain: an in-depth look at survivors’ reports of impact on work, social networks, and health care response. J Cancer Surviv. 2009;3(4):223–32.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Dietrich JHR, Yang Y, Mayer-Proschel M, Noble M. CNS progenitor cells and oligodendrocyres are targets of chemotherapeutic agents in vitro and in vivo. J Biol. 2006;5:22.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Ahles TA, Saykin AJ. Candidate mechanisms for chemotherapy-induced cognitive changes. Nat Rev Cancer. 2007;7(3):192–201.PubMedPubMedCentralGoogle Scholar
  11. 11.
    von Zglinicki T. Oxidative stress shortens telomeres. Trends Biochem Sci. 2002;27(7):339–44.Google Scholar
  12. 12.
    Meyers CA, Albitar M, Estey E. Cognitive impairment, fatigue, and cytokine levels in patients with acute myelogenous leukemia or myelodysplastic syndrome. Cancer. 2005;104(4):788–93.PubMedGoogle Scholar
  13. 13.
    Kelley KW, Bluthe RM, Dantzer R, Zhou JH, Shen WH, Johnson RW, et al. Cytokine-induced sickness behavior. Brain Behav Immun. 2003;17(Suppl 1):112-8.Google Scholar
  14. 14.
    Ramassamy C, Averill D, Beffert U, Bastianetto S, Theroux L, Lussier-Cacan S, et al. Oxidative damage and protection by antioxidants in the frontal cortex of Alzheimer’s disease is related to the apolipoprotein E genotype. Free Radic Biol Med. 1999;27(5–6):544–53.PubMedGoogle Scholar
  15. 15.
    Schultz W. Getting formal with dopamine and reward. Neuron. 2002;36(2):241–63.PubMedGoogle Scholar
  16. 16.
    Bäckman L, Nyberg L, Lindenberger U, Li SC, Farde L. The correlative triad among aging, dopamine, and cognition: current status and future prospects. Neurosci Biobehav Rev. 2006;30(6):791–807.PubMedGoogle Scholar
  17. 17.
    Kraft JC, Osterhaus GL, Ortiz AN, Garris PA, Johnson MA. In vivo dopamine release and uptake impairments in rats treated with 3-nitropropionic acid. Neuroscience. 2009;161(3):940–9.PubMedGoogle Scholar
  18. 18.
    Ortiz AN, Kurth BJ, Osterhaus GL, Johnson MA. Dysregulation of intracellular dopamine stores revealed in the R6/2 mouse striatum. J Neurochem. 2010;112(3):755–61.PubMedGoogle Scholar
  19. 19.
    Ortiz AN, Oien DB, Moskovitz J, Johnson MA. Quantification of reserve pool dopamine in methionine sulfoxide reductase A null mice. Neuroscience. 2011;177:223–9.PubMedPubMedCentralGoogle Scholar
  20. 20.
    Johnson MARV, Miller CE, Wightman RM. Dopamine release is severely compromised in the R6/2 mouse model of Huntington’s disease. J Neurochem. 2006;97:737–46.PubMedGoogle Scholar
  21. 21.
    Masliah E, Rockenstein E, Veinbergs I, Mallory M, Hashimoto M, Takeda A, et al. Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. Science. 2000;287(5456):1265–9.PubMedGoogle Scholar
  22. 22.
    Morgan DG, May PC, Finch CE. Dopamine and serotonin systems in human and rodent brain: effects of age and neurodegenerative disease. J Am Geriatr Soc. 1987;35(4):334–45.PubMedGoogle Scholar
  23. 23.
    Kung HF, Kung MP, Wey SP, Lin KJ, Yen TC. Clinical acceptance of a molecular imaging agent: a long march with [99mTc]TRODAT. Nucl Med Biol. 2007;34(7):787–9.PubMedGoogle Scholar
  24. 24.
    Van Laere K, Everaert L, Annemans L, Gonce M, Vandenberghe W, Vander Borght T. The cost effectiveness of 123I-FP-CIT SPECT imaging in patients with an uncertain clinical diagnosis of parkinsonism. Eur J Nucl Med Mol Imaging. 2008;35(7):1367–76.PubMedGoogle Scholar
  25. 25.
    Cheung YT, Ng T, Shwe M, Ho HK, Foo KM, Cham MT, et al. Association of proinflammatory cytokines and chemotherapy-associated cognitive impairment in breast cancer patients: a multi-centered, prospective, cohort study. Ann Oncol. 2015;26(7):1446–51.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Wagner LISJ, Butt Z, Lai JS, Cella D. Measuring patient self-reported cognitive function: development of the functional assessment of cancer therapy–cognitive function instrument. J Support Oncol. 2009;7:W32–W9.Google Scholar
  27. 27.
    Lima MS, Beria JU, Tomasi E, Conceicao AT, Mari JJ. Stressful life events and minor psychiatric disorders: an estimate of the population attributable fraction in a Brazilian community-based study. Int J Psychiatry Med. 1996;26(2):211–22.PubMedGoogle Scholar
  28. 28.
    Mari JJ. Psychiatric morbidity in three primary medical care clinics in the city of Sao Paulo. Issues on the mental health of the urban poor. Soc Psychiatry. 1987;22(3):129–38.PubMedGoogle Scholar
  29. 29.
    Shimizu S, Namioka N, Hirose D, Kanetaka H, Hirao K, Hatanaka H, et al. Comparison of diagnostic utility of semi-quantitative analysis for DAT-SPECT for distinguishing DLB from AD. J Neurol Sci. 2017;377:50–4.PubMedGoogle Scholar
  30. 30.
    Kaplan SV, Limbocker RA, Gehringer RC, Divis JL, Osterhaus GL, Newby MD, et al. Impaired brain dopamine and serotonin release and uptake in wistar rats following treatment with carboplatin. ACS Chem Neurosci. 2016;7(6):689–99.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Staat KSM. The phenomenon of chemobrain. Clin J Oncol Nurs. 2005;9:713–21.PubMedGoogle Scholar
  32. 32.
    Kaiser J, Bledowski C, Dietrich J. Neural correlates of chemotherapy-related cognitive impairment. Cortex. 2014;54:33–50.PubMedGoogle Scholar
  33. 33.
    Anderson-Hanley C, Sherman ML, Riggs R, Agocha VB, Compas BE. Neuropsychological effects of treatments for adults with cancer: a meta-analysis and review of the literature. J Int Neuropsychol Soc. 2003;9(7):967–82.PubMedGoogle Scholar
  34. 34.
    Merriman JD, Von Ah D, Miaskowski C, Aouizerat BE. Proposed mechanisms for cancer- and treatment-related cognitive changes. Semin Oncol Nurs. 2013;29(4):260–9.PubMedGoogle Scholar
  35. 35.
    Wefel JS, Kesler SR, Noll KR, Schagen SB. Clinical characteristics, pathophysiology, and management of noncentral nervous system cancer-related cognitive impairment in adults. CA Cancer J Clin. 2015;65(2):123–38.PubMedGoogle Scholar
  36. 36.
    Seigers RSS, Van Tellingen O, Dietrich J. Chemotherapy-related cognitive dysfunction: current animal studies and future directions. Brain Imaging Behav. 2013;7:453–9.PubMedGoogle Scholar
  37. 37.
    Evenden J. Cognitive impairments and cancer chemotherapy: translational research at a crossroads. Life Sci. 2013;93(17):589–95.PubMedGoogle Scholar
  38. 38.
    Shilling V, Jenkins V. Self-reported cognitive problems in women receiving adjuvant therapy for breast cancer. Eur J Oncol Nurs. 2007;11(1):6–15.PubMedGoogle Scholar
  39. 39.
    Von Ah D, Tallman EF. Perceived cognitive function in breast cancer survivors: evaluating relationships with objective cognitive performance and other symptoms using the functional assessment of cancer therapy-cognitive function instrument. J Pain Symptom Manag. 2015;49(4):697–706.Google Scholar
  40. 40.
    Tanimukai H. Prevalence of cognitive impairments following chemotherapy and its relationship to depression in Japanese breast cancer survivors: an exploratory study. Int J Complement Altern Med. 2018;11(2):145–9.Google Scholar
  41. 41.
    Backman L, Waris O, Johansson J, Andersson M, Rinne JO, Alakurtti K, et al. Increased dopamine release after working-memory updating training: Neurochemical correlates of transfer. Sci Rep. 2017;7(1):7160.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Iodice P, Ferrante C, Brunetti L, Cabib S, Protasi F, Walton ME, et al. Fatigue modulates dopamine availability and promotes flexible choice reversals during decision making. Sci Rep. 2017;7(1):535.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Bäckman L, Ginovart N, Dixon RA, Wahlin TB, Wahlin A, Halldin C, et al. Age-related cognitive deficits mediated by changes in the striatal dopamine system. Am J Psychiatry. 2000;157(4):635–7.PubMedGoogle Scholar
  44. 44.
    Gerfen CR. The neostriatal mosaic: multiple levels of compartmental organization in the basal ganglia. Annu Rev Neurosci. 1992;15:285–320.PubMedGoogle Scholar
  45. 45.
    Ferguson SM, Eskenazi D, Ishikawa M, Wanat MJ, Phillips PE, Dong Y, et al. Transient neuronal inhibition reveals opposing roles of indirect and direct pathways in sensitization. Nat Neurosci. 2011;14(1):22–4.PubMedGoogle Scholar
  46. 46.
    Hikosaka O, Takikawa Y, Kawagoe R. Role of the basal ganglia in the control of purposive saccadic eye movements. Physiol Rev. 2000;80(3):953–78.PubMedGoogle Scholar
  47. 47.
    Monje M, Dietrich J. Cognitive side effects of cancer therapy demonstrate a functional role for adult neurogenesis. Behav Brain Res. 2012;227(2):376–9.PubMedGoogle Scholar
  48. 48.
    Huang WS, Lin SZ, Lin JC, Wey SP, Ting G, Liu RS. Evaluation of early-stage Parkinson’s disease with 99mTc-TRODAT-1 imaging. J Nucl Med. 2001;42(9):1303–8.PubMedGoogle Scholar
  49. 49.
    Yin TK, Lee BF, Yang YK, Chiu NT. Differences of various region-of-interest methods for measuring dopamine transporter availability using 99mTc-TRODAT-1 SPECT. Sci World J. 2014;2014:837439.Google Scholar
  50. 50.
    Wefel JS, Saleeba AK, Buzdar AU, Meyers CA. Acute and late onset cognitive dysfunction associated with chemotherapy in women with breast cancer. Cancer. 2010;116(14):3348–56.PubMedGoogle Scholar
  51. 51.
    Briones TWJ, Wadowska M. Chronic neurpinflammation and cognitive impairment following transient global cerebral eschemia: role of fractalkine/CX3CR1signaling. J Neuroinflammation. 2014;11:3.Google Scholar
  52. 52.
    Holtbernd F, Ma Y, Peng S, Schwartz F, Timmermann L, Kracht L, et al. Dopaminergic correlates of metabolic network activity in Parkinson’s disease. Hum Brain Mapp. 2015;36(9):3575–85.PubMedGoogle Scholar
  53. 53.
    Aluise CD, Miriyala S, Noel T, Sultana R, Jungsuwadee P, Taylor TJ, et al. 2-Mercaptoethane sulfonate prevents doxorubicin-induced plasma protein oxidation and TNF-alpha release: implications for the reactive oxygen species-mediated mechanisms of chemobrain. Free Radic Biol Med. 2011;50(11):1630–8.PubMedGoogle Scholar
  54. 54.
    Myers JS. The possible role of cytokines in chemotherapy-induced cognitive deficits. Adv Exp Med Biol. 2010;678:119–23.PubMedGoogle Scholar
  55. 55.
    Stemmer SM, Stears JC, Burton BS, Jones RB, Simon JH. White matter changes in patients with breast cancer treated with high-dose chemotherapy and autologous bone marrow support. AJNR Am J Neuroradiol. 1994;15(7):1267–73.PubMedGoogle Scholar
  56. 56.
    Deprez SAF, Yigit R, et al. Chemotherapy-induced structural changes in cerebral white matter its correlation with impaired cognitive functioning in breast cancer patients. Hum Brain Mapp. 2011;32:580–493.Google Scholar
  57. 57.
    Deprez S, Amant F, Smeets A, Peeters R, Leemans A, Van Hecke W, et al. Longitudinal assessment of chemotherapy-induced structural changes in cerebral white matter and its correlation with impaired cognitive functioning. J Clin Oncol. 2012;30(3):274–81.PubMedGoogle Scholar
  58. 58.
    Silverman DH, Dy CJ, Castellon SA, Lai J, Pio BS, Abraham L, et al. Altered frontocortical, cerebellar, and basal ganglia activity in adjuvant-treated breast cancer survivors 5–10 years after chemotherapy. Breast Cancer Res Treat. 2007;103(3):303–11.PubMedGoogle Scholar
  59. 59.
    Nudelman KN, Wang Y, McDonald BC, Conroy SK, Smith DJ, West JD, et al. Altered cerebral blood flow one month after systemic chemotherapy for breast cancer: a prospective study using pulsed arterial spin labeling MRI perfusion. PLoS One. 2014;9(5):e96713.PubMedPubMedCentralGoogle Scholar
  60. 60.
    Chuang C, Constantino A, Balmaceda C, Eidelberg D, Frucht SJ. Chemotherapy-induced parkinsonism responsive to levodopa: an underrecognized entity. Mov Disord. 2003;18(3):328–31.PubMedGoogle Scholar
  61. 61.
    Bruno J, Hosseini SM, Kesler S. Altered resting state functional brain network topology in chemotherapy-treated breast cancer survivors. Neurobiol Dis. 2012;48(3):329–38.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Deprez S, Amant F, Yigit R, Porke K, Verhoeven J, Van den Stock J, et al. Chemotherapy-induced structural changes in cerebral white matter and its correlation with impaired cognitive functioning in breast cancer patients. Hum Brain Mapp. 2011;32(3):480–93.PubMedGoogle Scholar
  63. 63.
    Inagaki M, Yoshikawa E, Matsuoka Y, Sugawara Y, Nakano T, Akechi T, et al. Smaller regional volumes of brain gray and white matter demonstrated in breast cancer survivors exposed to adjuvant chemotherapy. Cancer. 2007;109(1):146–56.PubMedGoogle Scholar
  64. 64.
    de Ruiter MB, Reneman L, Boogerd W, Veltman DJ, Caan M, Douaud G, et al. Late effects of high-dose adjuvant chemotherapy on white and gray matter in breast cancer survivors: converging results from multimodal magnetic resonance imaging. Hum Brain Mapp. 2012;33(12):2971–83.PubMedGoogle Scholar
  65. 65.
    Abraham JHM, Moran M, Filburn S, Lemiuex S, Kuwabara H. Adjuvant chemotherapy for breast cancer: effects on cerebral white matter seen in diffusio tensor imaging. Clin Breast Cancer. 2008;8:88–91.PubMedGoogle Scholar
  66. 66.
    Conroy SKMB, Smith DJ, et al. Alterations in brain structure in breast cancer survivors: effect of post-chemotherapy interval and relation to oxidative DNA damage. Breast Cancer Res Treat. 2013;137:493–502.PubMedGoogle Scholar
  67. 67.
    Huang CK, Wu J, Cheng KY, Pan LK. Optimization of imaging parameters for SPECT scans of [99mTc]TRODAT-1 using Taguchi analysis. PLoS One. 2015;10(3):e0113817.PubMedPubMedCentralGoogle Scholar
  68. 68.
    Felicio AC, Godeiro-Junior C, Shih MC, Borges V, Silva SM, Aguiar PeC, et al. Evaluation of patients with clinically unclear Parkinsonian syndromes submitted to brain SPECT imaging using the technetium-99m labeled tracer TRODAT-1. J Neurol Sci. 2010;291(1–2):64–8.PubMedGoogle Scholar
  69. 69.
    Bor-Seng-Shu E, Felicio AC, Braga-Neto P, Batista IR, Paiva WS, de Andrade DC, et al. Dopamine transporter imaging using 99mTc-TRODAT-1 SPECT in Parkinson’s disease. Med Sci Monit. 2014;20:1413–8.PubMedPubMedCentralGoogle Scholar

Copyright information

© The Japanese Society of Nuclear Medicine 2019

Authors and Affiliations

  • Taise Vitor
    • 1
    Email author
  • Elisa H. Kozasa
    • 1
  • Rodrigo A. Bressan
    • 2
  • Shirley S. Lacerda
    • 1
  • Guilherme C. Campos Neto
    • 1
  • Ilza Rosa Batista
    • 2
  • Luiz Henrique Gebrim
    • 3
  • Lorenzo Cohen
    • 4
  • Edson Amaro
    • 1
  • Andre C. Felicio
    • 1
  1. 1.Imaging DepartmentHospital Israelita Albert EinsteinSão PauloBrazil
  2. 2.Interdisciplinary Laboratory of Neuroimaging and CognitionFederal University of São PauloSão PauloBrazil
  3. 3.Pérola Byington HospitalSão PauloBrazil
  4. 4.Department of Palliative, Rehabilitation, and Integrative MedicineThe University of Texas, MD Anderson Cancer CenterHoustonUSA

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