Brain Imaging and Behavior

, Volume 7, Issue 4, pp 501–510 | Cite as

Elevated prefrontal myo-inositol and choline following breast cancer chemotherapy

  • Shelli R. KeslerEmail author
  • Christa Watson
  • Della Koovakkattu
  • Clement Lee
  • Ruth O’Hara
  • Misty L. Mahaffey
  • Jeffrey S. Wefel
SI: Neuroimaging Studies of Cancer and Cancer Treatment


Breast cancer survivors are at increased risk for cognitive dysfunction, which reduces quality of life. Neuroimaging studies provide critical insights regarding the mechanisms underlying these cognitive deficits as well as potential biologic targets for interventions. We measured several metabolite concentrations using 1H magnetic resonance spectroscopy as well as cognitive performance in 19 female breast cancer survivors and 17 age-matched female controls. Women with breast cancer were all treated with chemotherapy. Results indicated significantly increased choline (Cho) and myo-inositol (mI) with correspondingly decreased N-acetylaspartate (NAA)/Cho and NAA/mI ratios in the breast cancer group compared to controls. The breast cancer group reported reduced executive function and memory, and subjective memory ability was correlated with mI and Cho levels in both groups. These findings provide preliminary evidence of an altered metabolic profile that increases our understanding of neurobiologic status post-breast cancer and chemotherapy.


MR Spectroscopy Breast Cancer Cognition Prefrontal Cortex Chemotherapy 


  1. Aghakhani, A. and Chan, E.K., 2007. Test Reviews: Bracken, B. A., & Howell, K. (2004). Clinical Assessment of Depression. Odessa, FL: Psychological Assessment Resources. Journal of Psychoeducational Assessment. 25, 416–422.Google Scholar
  2. Ahles, T. A., Saykin, A. J., McDonald, B. C., Li, Y., Furstenberg, C. T., Hanscom, B. S., Mulrooney, T. J., Schwartz, G. N., & Kaufman, P. A. (2010). Longitudinal assessment of cognitive changes associated with adjuvant treatment for breast cancer: impact of age and cognitive reserve. Journal of Clinical Oncology., 28, 4434–4440.PubMedCrossRefGoogle Scholar
  3. Arnsten, A. F. (2011). Prefrontal cortical network connections: key site of vulnerability in stress and schizophrenia. International Journal of Developmental Neuroscience: the official Journal of the International Society for Developmental Neuroscience., 29, 215–223.CrossRefGoogle Scholar
  4. Benedict, R. H. B., Schretlen, D., Groninger, L., & Brandt, J. (1998). Hopkins verbal learning test – revised: normative data and analysis of inter-form and test-retest reliability. The Clinical Neuropsychologist., 12, 43–55.CrossRefGoogle Scholar
  5. Boripuntakul, S., Kothan, S., Methapatara, P., Munkhetvit, P., & Sungkarat, S. (2012). Short-term effects of cognitive training program for individuals with amnestic mild cognitive impairment: a pilot study. Physical & Occupational Therapy in Geriatrics., 30, 138–149.CrossRefGoogle Scholar
  6. Bozgeyik, Z., Burakgazi, G., Sen, Y., & Ogur, E. (2008). Age-related metabolic changes in the corpus callosum: assessment with MR spectroscopy. Diagnostic and Interventional Radiology., 14, 173–176.PubMedGoogle Scholar
  7. Brown, M. S., Stemmer, S. M., Simon, J. H., Stears, J. C., Jones, R. B., Cagnoni, P. J., & Sheeder, J. L. (1998). White matter disease induced by high-dose chemotherapy: longitudinal study with MR imaging and proton spectroscopy. AJNR. American Journal of Neuroradiology., 19, 217–221.PubMedGoogle Scholar
  8. Bruno, J., Hosseini, S. M., & Kesler, S. (2012). Altered resting state functional brain network topology in chemotherapy-treated breast cancer survivors. Neurobiol Dis., 48, 329–338.PubMedCentralPubMedCrossRefGoogle Scholar
  9. Castellon, S. A., Ganz, P. A., Bower, J. E., Petersen, L., Abraham, L., & Greendale, G. A. (2004). Neurocognitive performance in breast cancer survivors exposed to adjuvant chemotherapy and tamoxifen. J Clin Exp Neuropsychol., 26, 955–969.PubMedCrossRefGoogle Scholar
  10. Chang, K., Adleman, N., Dienes, K., Barnea-Goraly, N., Reiss, A., & Ketter, T. (2003). Decreased N-acetylaspartate in children with familial bipolar disorder. Biol Psychiatry., 53, 1059–1065.PubMedCrossRefGoogle Scholar
  11. Chang, K., Karchemskiy, A., Kelley, R., Howe, M., Garrett, A., Adleman, N., & Reiss, A. (2009). Effect of divalproex on brain morphometry, chemistry, and function in youth at high-risk for bipolar disorder: a pilot study. J Child Adolesc Psychopharmacol., 19, 51–59.PubMedCrossRefGoogle Scholar
  12. de Ruiter, M.B., Reneman, L., Boogerd, W., Veltman, D.J., Caan, M., Douaud, G., Lavini, C., Linn, S.C., Boven, E., van Dam, F.S. and Schagen, S.B. (2011a). 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.Google Scholar
  13. de Ruiter, M. B., Reneman, L., Boogerd, W., Veltman, D. J., van Dam, F. S., Nederveen, A. J., Boven, E., & Schagen, S. B. (2011b). Cerebral hyporesponsiveness and cognitive impairment 10 years after chemotherapy for breast cancer. Hum Brain Mapp., 32, 1206–1219.PubMedCrossRefGoogle Scholar
  14. Deprez, S., Amant, F., Yigit, R., Porke, K., Verhoeven, J., Van den Stock, J., Smeets, A., Christiaens, M. R., Leemans, A., Van Hecke, W., Vandenberghe, J., Vandenbulcke, M., & Sunaert, S. (2011). Chemotherapy-induced structural changes in cerebral white matter and its correlation with impaired cognitive functioning in breast cancer patients. Human Brain Mapping., 32, 480–493.PubMedCrossRefGoogle Scholar
  15. Deprez, S., Amant, F., Smeets, A., Peeters, R., Leemans, A., Van Hecke, W., Verhoeven, J. S., Christiaens, M. R., Vandenberghe, J., Vandenbulcke, M., & Sunaert, S. (2012). Longitudinal assessment of chemotherapy-induced structural changes in cerebral white matter and its correlation with impaired cognitive functioning. J Clin Oncol., 30, 274–281.PubMedCrossRefGoogle Scholar
  16. Diamond, A. (2011). Biological and social influences on cognitive control processes dependent on prefrontal cortex. Progress in Brain Research., 189, 319–339.PubMedGoogle Scholar
  17. Elliott, R. (2003). Executive functions and their disorders. British Medical Bulletin., 65, 49–59.PubMedCrossRefGoogle Scholar
  18. Ernst, T., Chang, L., Cooray, D., Salvador, C., Jovicich, J., Walot, I., Boone, K., & Chlebowski, R. (2002). The effects of tamoxifen and estrogen on brain metabolism in elderly women. J Natl Cancer Inst., 94, 592–597.PubMedCrossRefGoogle Scholar
  19. Francis, P. T. (2003). Glutamatergic systems in Alzheimer’s disease. Int J Geriatr Psychiatry., 18, S15–21.PubMedCrossRefGoogle Scholar
  20. Gamper, N., & Shapiro, M. S. (2007). Regulation of ion transport proteins by membrane phosphoinositides. Nature reviews. Neuroscience., 8, 921–934.PubMedGoogle Scholar
  21. Ganz, P. A., Bower, J. E., Kwan, L., Castellon, S. A., Silverman, D. H. S., Geist, C., Breen, E. C., Irwin, M. R., & Cole, S. W. (2013). Does tumor necrosis factor-alpha (TNF-α) play a role in post-chemotherapy cerebral dysfunction? Brain, Behavior, and Immunity., 30, S99–S108.PubMedCrossRefGoogle Scholar
  22. Heaton, R. K. (2004). Wisconsin card sorting test computer version 4 - research edition (WCST:CV4). Odessa: Psychological Assessment Resources.Google Scholar
  23. Henigsberg, N., Kalember, P., Hrabac, P., Rados, M., Bajs, M., Kovavic, Z., Loncar, M., & Madzar, T. (2011). 1-H MRS changes in dorsolateral prefrontal cortex after donepezil treatment in patients with mild to moderate Alzheimer’s disease. Collegium Antropologicum., 35(Suppl 1), 159–162.PubMedGoogle Scholar
  24. Homack, S., Lee, D., & Riccio, C. A. (2005). Test review: Delis-Kaplan executive function system. J Clin Exp Neuropsychol., 27, 599–609.PubMedCrossRefGoogle Scholar
  25. Hosseini, S. M., Koovakkattu, D., & Kesler, S. R. (2012). Altered small-world properties of gray matter networks in breast cancer. BMC Neurol., 12, 28.PubMedCentralPubMedCrossRefGoogle Scholar
  26. Janelsins, M. C., Kohli, S., Mohile, S. G., Usuki, K., Ahles, T. A., & Morrow, G. R. (2011). An update on cancer- and chemotherapy-related cognitive dysfunction: current status. Seminars in Oncology., 38, 431–438.PubMedCentralPubMedCrossRefGoogle Scholar
  27. Jansen, C. E., Miaskowski, C., Dodd, M., Dowling, G., & Kramer, J. (2005). A metaanalysis of studies of the effects of cancer chemotherapy on various domains of cognitive function. Cancer., 104, 2222–2233.PubMedCrossRefGoogle Scholar
  28. Joshi, G., Aluise, C. D., Cole, M. P., Sultana, R., Pierce, W. M., Vore, M., St Clair, D. K., & Butterfield, D. A. (2010). Alterations in brain antioxidant enzymes and redox proteomic identification of oxidized brain proteins induced by the anti-cancer drug adriamycin: implications for oxidative stress-mediated chemobrain. Neuroscience., 166, 796–807.PubMedCentralPubMedCrossRefGoogle Scholar
  29. Kesler, S. R., Bennett, F. C., Mahaffey, M. L., & Spiegel, D. (2009a). Regional brain activation during verbal declarative memory in metastatic breast cancer. Clin Cancer Res., 15, 6665–6673.PubMedCentralPubMedCrossRefGoogle Scholar
  30. Kesler, S. R., Lightbody, A. A., & Reiss, A. L. (2009b). Cholinergic dysfunction in fragile X syndrome and potential intervention: a preliminary 1H MRS study. Am J Med Genet A., 149A, 403–407.PubMedCentralPubMedCrossRefGoogle Scholar
  31. Kesler, S. R., Kent, J. S., & O’Hara, R. (2011). Prefrontal cortex and executive function impairments in primary breast cancer. Arch Neurol., 68, 1447–1453.PubMedCentralPubMedCrossRefGoogle Scholar
  32. Kesler, S., Janelsins, M., Koovakkattu, D., Palesh, O., Mustian, K., Morrow, G., & Dhabhar, F. S. (2013). Reduced hippocampal volume and verbal memory performance associated with interleukin-6 and tumor necrosis factor-alpha levels in chemotherapy-treated breast cancer survivors. Brain Behav Immun., 30, S109–S116.PubMedCentralPubMedCrossRefGoogle Scholar
  33. Koppelmans, V., de Ruiter, M.B., van der Lijn, F., Boogerd, W., Seynaeve, C., van der Lugt, A., Vrooman, H., Niessen, W.J., Breteler, M.M. and Schagen, S.B. (2011). Global and focal brain volume in long-term breast cancer survivors exposed to adjuvant chemotherapy. Breast Cancer Res Treat.Google Scholar
  34. Leh, S. E., Petrides, M., & Strafella, A. P. (2010). The neural circuitry of executive functions in healthy subjects and Parkinson’s disease. Neuropsychopharmacology., 35, 70–85.PubMedCrossRefGoogle Scholar
  35. Lemaitre, H., Goldman, A.L., Sambataro, F., Verchinski, B.A., Meyer-Lindenberg, A., Weinberger, D.R. and Mattay, V.S. (2010). Normal age-related brain morphometric changes: nonuniformity across cortical thickness, surface area and gray matter volume? Neurobiology of aging.Google Scholar
  36. Maddock, R.J. and Buonocore, M.H. (2012). MR spectroscopic studies of the brain in psychiatric disorders. Current topics in behavioral neurosciences.Google Scholar
  37. McDonald, B. C., Conroy, S. K., Ahles, T. A., West, J. D., & Saykin, A. J. (2010). Gray matter reduction associated with systemic chemotherapy for breast cancer: a prospective MRI study. Breast Cancer Research and Treatment., 123, 819–828.PubMedCentralPubMedCrossRefGoogle Scholar
  38. McDonald, B.C., Conroy, S.K., Ahles, T.A., West, J.D. and Saykin, A.J. (2012a). Alterations in brain activation during working memory processing associated with breast cancer and treatment: a prospective functional magnetic resonance imaging study. J Clin Oncol.Google Scholar
  39. McDonald, B.C., Conroy, S.K., Smith, D.J., West, J.D. and Saykin, A.J. (2012b). Frontal gray matter reduction after breast cancer chemotherapy and association with executive symptoms: A replication and extension study. Brain Behav Immun.Google Scholar
  40. NCI. (2012, 09/24/2012). “Breast Cancer Risk in American Women.” Retrieved 01/30/2013, 2013, from
  41. Newman, E. L., Gupta, K., Climer, J. R., Monaghan, C. K., & Hasselmo, M. E. (2012). Cholinergic modulation of cognitive processing: insights drawn from computational models. Front Behav Neurosci., 6, 24.PubMedCentralPubMedGoogle Scholar
  42. Ouimet, L. A., Stewart, A., Collins, B., Schindler, D., & Bielajew, C. (2009). Measuring neuropsychological change following breast cancer treatment: an analysis of statistical models. J Clin Exp Neuropsychol., 31, 73–89.PubMedCrossRefGoogle Scholar
  43. Prescot, A. P., Locatelli, A. E., Renshaw, P. F., & Yurgelun-Todd, D. A. (2011). Neurochemical alterations in adolescent chronic marijuana smokers: a proton MRS study. Neuroimage., 57, 69–75.PubMedCentralPubMedCrossRefGoogle Scholar
  44. Provencher, S. (2001). Automatic quantitation of localized in vivo 1H spectra with LCModel. NMR in Biomed., 14, 260–264.CrossRefGoogle Scholar
  45. Quesnel, C., Savard, J., & Ivers, H. (2009). Cognitive impairments associated with breast cancer treatments: results from a longitudinal study. Breast Cancer Res Treat., 116, 113–123.PubMedCrossRefGoogle Scholar
  46. Roth, R. M., Isquith, P. K., & Gioia, G. (2005). Behavioral rating inventory of executive function - adult version. Lutz: Psychological Assessment Resources.Google Scholar
  47. Schifitto, G., Deng, L., Yeh, T. M., Evans, S. R., Ernst, T., Zhong, J., & Clifford, D. (2011). Clinical, laboratory, and neuroimaging characteristics of fatigue in HIV-infected individuals. J Neurovirol., 17, 17–25.PubMedCentralPubMedCrossRefGoogle Scholar
  48. Schneider, P., Weber-Fahr, W., Schweinfurth, N., Ho, Y. J., Sartorius, A., Spanagel, R., & Pawlak, C. R. (2012). Central metabolite changes and activation of microglia after peripheral interleukin-2 challenge. Brain Behav Immun., 26, 277–283.PubMedCrossRefGoogle Scholar
  49. Seruga, B., Zhang, H., Bernstein, L. J., & Tannock, I. F. (2008). Cytokines and their relationship to the symptoms and outcome of cancer. Nat Rev Cancer., 8, 887–899.PubMedCrossRefGoogle Scholar
  50. Silverman, D. H., Dy, C. J., Castellon, S. A., Lai, J., Pio, B. S., Abraham, L., Waddell, K., Petersen, L., Phelps, M. E., & Ganz, P. A. (2007). Altered frontocortical, cerebellar, and basal ganglia activity in adjuvant-treated breast cancer survivors 5–10 years after chemotherapy. Breast Cancer Res Treat., 103, 303–311.PubMedCrossRefGoogle Scholar
  51. Stern, Y. (2009). Cognitive reserve. Neuropsychologia., 47, 2015–2028.PubMedCentralPubMedCrossRefGoogle Scholar
  52. Stern, R. A., & White, T. (2005). NAB Categories Test. Lutz: Psychological Assessment Resources.Google Scholar
  53. Stilley, C. S., Bender, C. M., Dunbar-Jacob, J., Sereika, S., & Ryan, C. M. (2010). The impact of cognitive function on medication management: three studies. Health Psychology: official Journal of the Division of Health Psychology, American Psychological Association., 29, 50–55.CrossRefGoogle Scholar
  54. Tangpong, J., Cole, M. P., Sultana, R., Joshi, G., Estus, S., Vore, M., St Clair, W., Ratanachaiyavong, S., St Clair, D. K., & Butterfield, D. A. (2006). Adriamycin-induced, TNF-alpha-mediated central nervous system toxicity. Neurobiology of Disease., 23, 127–139.PubMedCrossRefGoogle Scholar
  55. Tangpong, J., Cole, M. P., Sultana, R., Estus, S., Vore, M., St Clair, W., Ratanachaiyavong, S., St Clair, D. K., & Butterfield, D. A. (2007). Adriamycin-mediated nitration of manganese superoxide dismutase in the central nervous system: insight into the mechanism of chemobrain. J Neurochem., 100, 191–201.PubMedCrossRefGoogle Scholar
  56. Tayebati, S. K., Tomassoni, D., Di Stefano, A., Sozio, P., Cerasa, L. S., & Amenta, F. (2011). Effect of choline-containing phospholipids on brain cholinergic transporters in the rat. Journal of the Neurological Sciences., 302, 49–57.PubMedCrossRefGoogle Scholar
  57. Troyer, A. K., & Rich, J. B. (2002). Psychometric properties of a new metamemory questionnaire for older adults. The Journals of Gerontology Series B: Psychological Sciences and Social Sciences., 57, P19–P27.CrossRefGoogle Scholar
  58. Vardy, J. (2009). Cognitive function in breast cancer survivors. Cancer Treat Res., 151, 387–419.PubMedCrossRefGoogle Scholar
  59. Vehmanen, L., Elomaa, I., Blomqvist, C., & Saarto, T. (2006). Tamoxifen treatment after adjuvant chemotherapy has opposite effects on bone mineral density in premenopausal patients depending on menstrual status. Journal of Clinical Oncology: official Journal of the American Society of Clinical Oncology., 24, 675–680.CrossRefGoogle Scholar
  60. Von Ah, D., Carpenter, J. S., Saykin, A., Monahan, P., Wu, J., Yu, M., Rebok, G., Ball, K., Schneider, B., Weaver, M., Tallman, E., & Unverzagt, F. (2012). Advanced cognitive training for breast cancer survivors: a randomized controlled trial. Breast Cancer Res Treat., 135, 799–809.CrossRefGoogle Scholar
  61. Wang, T., Xiao, S., Li, X., Ding, B., Ling, H., Chen, K. and Fang, Y. (2011). Using proton magnetic resonance spectroscopy to identify mild cognitive impairment. International psychogeriatrics/IPA. 1–9.Google Scholar
  62. Wechsler, D. (2008). Wechsler adult intelligence scale fourth edition. San Antonio: The Psychological Corporation.Google Scholar
  63. Wefel, J. S., & Schagen, S. B. (2012). Chemotherapy-related cognitive dysfunction. Curr Neurol Neurosci Rep., 12, 267–275.PubMedCrossRefGoogle Scholar
  64. Wefel, J. S., Lenzi, R., Theriault, R. L., Davis, R. N., & Meyers, C. A. (2004). The cognitive sequelae of standard-dose adjuvant chemotherapy in women with breast carcinoma: results of a prospective, randomized, longitudinal trial. Cancer., 100, 2292–2299.PubMedCrossRefGoogle Scholar
  65. Wefel, J. S., Saleeba, A. K., Buzdar, A. U., & Meyers, C. A. (2010). Acute and late onset cognitive dysfunction associated with chemotherapy in women with breast cancer. Cancer., 116, 3348–3356.PubMedCrossRefGoogle Scholar
  66. Wefel, J. S., Vardy, J., Ahles, T., & Schagen, S. B. (2011). International cognition and cancer task force recommendations to harmonise studies of cognitive function in patients with cancer. The Lancet Oncology., 12, 703–708.PubMedCrossRefGoogle Scholar
  67. Winocur, G., Binns, M. A., & Tannock, I. (2011). Donepezil reduces cognitive impairment associated with anti-cancer drugs in a mouse model. Neuropharmacology., 61, 1222–1228.PubMedCrossRefGoogle Scholar
  68. Yang, B., Akhter, S., Chaudhuri, A., & Kanmogne, G. D. (2009). HIV-1 gp120 induces cytokine expression, leukocyte adhesion, and transmigration across the blood–brain barrier: modulatory effects of STAT1 signaling. Microvasc Res., 77, 212–219.PubMedCentralPubMedCrossRefGoogle Scholar
  69. Yorek, M. A., Dunlap, J. A., Thomas, M. J., Cammarata, P. R., Zhou, C., & Lowe, W. L., Jr. (1998). Effect of TNF-alpha on SMIT mRNA levels and myo-inositol accumulation in cultured endothelial cells. Am J Physiol., 274, C58–71.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Shelli R. Kesler
    • 1
    • 2
    Email author
  • Christa Watson
    • 1
    • 3
  • Della Koovakkattu
    • 1
  • Clement Lee
    • 1
  • Ruth O’Hara
    • 1
  • Misty L. Mahaffey
    • 2
  • Jeffrey S. Wefel
    • 4
  1. 1.Department of Psychiatry and Behavioral SciencesStanford UniversityStanfordUSA
  2. 2.Stanford Cancer InstitutePalo AltoUSA
  3. 3.Memory and Aging Center, Department of NeurologyUniversity of California at San FranciscoSan FranciscoUSA
  4. 4.Department of Neuro-OncologyUniversity of Texas M.D. Anderson Cancer CenterHoustonUSA

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