Brain Imaging and Behavior

, Volume 7, Issue 4, pp 436–452 | Cite as

Integrating imaging findings in evaluating the post-chemotherapy brain

  • K. L. Pomykala
  • M. B. de Ruiter
  • S. Deprez
  • B. C. McDonald
  • D. H. S. Silverman
SI: Neuroimaging Studies of Cancer and Cancer Treatment

Abstract

Cognitive complaints following cancer and cancer therapy are common. Many studies have investigated the effects of chemotherapy on the brain. However, the mechanisms for the associated cognitive impairment are not well understood. Some studies have also included brain imaging to investigate potential neurological substrates of cognitive changes. This review examines recent neuroimaging studies on cancer- and chemotherapy-related cognitive dysfunction in non-central nervous system cancers and compares findings across imaging modalities. Grey matter volume reductions and decreases in white matter integrity are seen after exposure to adjuvant chemotherapy for breast cancer, and functional studies have illuminated both hypo- and hyperactivations in many of the same regions months to years following therapy. These comparisons can assist in further characterizing the dysfunction reported by patients and contribute to a better understanding of the mechanisms involved.

Keywords

Functional magnetic resonance imaging Magnetic resonance imaging Positron emission tomography Diffusion tensor imaging Neuroimaging Chemotherapy Cognitive complaints 

References

  1. Abraham, J., Haut, M. W., Moran, M. T., Filburn, S., Lemiuex, S., & Kuwabara, H. (2008). Adjuvant chemotherapy for breast cancer: effects on cerebral white matter seen in diffusion tensor imaging. Clinical Breast Cancer, 8(1), 88–91. doi:10.3816/CBC.2008.n.007.PubMedCrossRefGoogle Scholar
  2. Ahles, T. A., & Saykin, A. J. (2007). Candidate mechanisms for chemotherapy-induced cognitive changes. [Research Support, N.I.H., Extramural Review]. Nature Reviews. Cancer, 7(3), 192–201. doi:10.1038/nrc2073.PubMedCentralPubMedCrossRefGoogle Scholar
  3. Ahles, T. A., Saykin, A. J., Furstenberg, C. T., Cole, B., Mott, L. A., Skalla, K., et al. (2002). Neuropsychologic impact of standard-dose systemic chemotherapy in long-term survivors of breast cancer and lymphoma. [Comparative Study Research Support, U.S. Gov’t, P.H.S.]. Journal of Clinical Oncology, 20(2), 485–493.PubMedCrossRefGoogle Scholar
  4. Baudino, B., D’Agata, F., Caroppo, P., Castellano, G., Cauda, S., Manfredi, M., et al. (2012). The chemotherapy long-term effect on cognitive functions and brain metabolism in lymphoma patients. The Quarterly Journal of Nuclear Medicine and Molecular Imaging, 56(6), 559–568.PubMedGoogle Scholar
  5. Bergouignan, L., Lefranc, J. P., Chupin, M., Morel, N., Spano, J. P., & Fossati, P. (2011). Breast cancer affects both the hippocampus volume and the episodic autobiographical memory retrieval. [Research Support, Non-U.S. Gov’t]. PLoS One, 6(10), e25349. doi:10.1371/journal.pone.0025349.PubMedCentralPubMedCrossRefGoogle Scholar
  6. Burstein, H. J. (2007). Cognitive side-effects of adjuvant treatments. [Review]. Breast, 16(Suppl 2), S166–S168. doi:10.1016/j.breast.2007.07.027.PubMedCrossRefGoogle Scholar
  7. Cabeza, R., & Nyberg, L. (2000). Imaging cognition II: an empirical review of 275 PET and fMRI studies. [Review]. Journal of Cognitive Neuroscience, 12(1), 1–47.PubMedCrossRefGoogle Scholar
  8. Chiaravalloti, A., Pagani, M., Di Pietro, B., Danieli, R., Tavolozza, M., Travascio, L., et al. (2013). Is cerebral glucose metabolism affected by chemotherapy in patients with Hodgkin’s lymphoma? Nuclear Medicine Communications, 34(1), 57–63. doi:10.1097/MNM.0b013e32835aa7de.PubMedCrossRefGoogle Scholar
  9. Cimprich, B., Reuter-Lorenz, P., Nelson, J., Clark, P. M., Therrien, B., Normolle, D., et al. (2010). Prechemotherapy alterations in brain function in women with breast cancer. [Research Support, Non-U.S. Gov’t]. Journal of Clinical and Experimental Neuropsychology, 32(3), 324–331. doi:10.1080/13803390903032537.PubMedCrossRefGoogle Scholar
  10. de Ruiter, M. B., Reneman, L., Boogerd, W., Veltman, D. J., Caan, M., Douaud, G., et al. (2012). Late effects of high-dose adjuvant chemotherapy on white and gray matter in breast cancer survivors: converging results from multimodal magnetic resonance imaging. [Research Support, Non-U.S. Gov’t]. Human Brain Mapping, 33(12), 2971–2983. doi:10.1002/hbm.21422.PubMedCrossRefGoogle Scholar
  11. de Ruiter, M. B., Reneman, L., Boogerd, W., Veltman, D. J., van Dam, F. S., Nederveen, A. J., et al. (2011). Cerebral hyporesponsiveness and cognitive impairment 10 years after chemotherapy for breast cancer. Human Brain Mapping, 32(8), 1206–1219. doi:10.1002/hbm.21102.PubMedCrossRefGoogle Scholar
  12. Deprez, S., Amant, F., Smeets, A., Peeters, R., Leemans, A., Van Hecke, W., et al. (2012). Longitudinal assessment of chemotherapy-induced structural changes in cerebral white matter and its correlation with impaired cognitive functioning. [Research Support, Non-U.S. Gov’t]. Journal of Clinical Oncology, 30(3), 274–281. doi:10.1200/JCO.2011.36.8571.PubMedCrossRefGoogle Scholar
  13. Deprez, S., Amant, F., Yigit, R., Porke, K., Verhoeven, J., Van den Stock, J., et al. (2011). Chemotherapy-induced structural changes in cerebral white matter and its correlation with impaired cognitive functioning in breast cancer patients. [Research Support, Non-U.S. Gov’t]. Human Brain Mapping, 32(3), 480–493. doi:10.1002/hbm.21033.PubMedCrossRefGoogle Scholar
  14. Dietrich, J., Monje, M., Wefel, J., & Meyers, C. (2008). Clinical patterns and biological correlates of cognitive dysfunction associated with cancer therapy. [Research Support, Non-U.S. Gov’t Review]. The Oncologist, 13(12), 1285–1295. doi:10.1634/theoncologist.2008-0130.PubMedCrossRefGoogle Scholar
  15. Dijkstra, J. B., Houx, P. J., & Jolles, J. (1999). Cognition after major surgery in the elderly: test performance and complaints. [Research Support, Non-U.S. Gov’t]. British Journal of Anaesthesia, 82(6), 867–874.PubMedCrossRefGoogle Scholar
  16. Dodds, C., & Allison, J. (1998). Postoperative cognitive deficit in the elderly surgical patient. [Review]. British Journal of Anaesthesia, 81(3), 449–462.PubMedCrossRefGoogle Scholar
  17. Eheman, C., Henley, S. J., Ballard-Barbash, R., Jacobs, E. J., Schymura, M. J., Noone, A. M., et al. (2012). Annual Report to the Nation on the status of cancer, 1975–2008, featuring cancers associated with excess weight and lack of sufficient physical activity. [Editorial Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, P.H.S.]. Cancer, 118(9), 2338–2366. doi:10.1002/cncr.27514.PubMedCrossRefGoogle Scholar
  18. Ferguson, R. J., & Ahles, T. A. (2003). Low neuropsychologic performance among adult cancer survivors treated with chemotherapy. [Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, P.H.S. Review]. Current Neurology and Neuroscience Reports, 3(3), 215–222.PubMedCrossRefGoogle Scholar
  19. Ferguson, R. J., McDonald, B. C., Saykin, A. J., & Ahles, T. A. (2007). Brain structure and function differences in monozygotic twins: possible effects of breast cancer chemotherapy. [Case Reports Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t Twin Study]. Journal of Clinical Oncology, 25(25), 3866–3870. doi:10.1200/JCO.2007.10.8639.PubMedCentralPubMedCrossRefGoogle Scholar
  20. Inagaki, M., Yoshikawa, E., Matsuoka, Y., Sugawara, Y., Nakano, T., Akechi, T., et al. (2007). Smaller regional volumes of brain gray and white matter demonstrated in breast cancer survivors exposed to adjuvant chemotherapy. [Comparative Study Research Support, Non-U.S. Gov’t]. Cancer, 109(1), 146–156. doi:10.1002/cncr.22368.PubMedCrossRefGoogle Scholar
  21. Kesler, S., Janelsins, M., Koovakkattu, D., Palesh, O., Mustian, K., Morrow, G., et al. (2012). Reduced hippocampal volume and verbal memory performance associated with interleukin-6 and tumor necrosis factor-alpha levels in chemotherapy-treated breast cancer survivors. Brain, Behavior, and Immunity. doi:10.1016/j.bbi.2012.05.017.PubMedCentralPubMedGoogle Scholar
  22. Kesler, S. R., Bennett, F. C., Mahaffey, M. L., & Spiegel, D. (2009). Regional brain activation during verbal declarative memory in metastatic breast cancer. [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t]. Clinical Cancer Research, 15(21), 6665–6673. doi:10.1158/1078-0432.CCR-09-1227.PubMedCentralPubMedCrossRefGoogle Scholar
  23. Kesler, S. R., Kent, J. S., & O’Hara, R. (2011). Prefrontal cortex and executive function impairments in primary breast cancer. [Comparative Study Research Support, N.I.H., Extramural]. Archives of Neurology, 68(11), 1447–1453. doi:10.1001/archneurol.2011.245.PubMedCentralPubMedCrossRefGoogle Scholar
  24. Koppelmans, V., Breteler, M. M., Boogerd, W., Seynaeve, C., Gundy, C., & Schagen, S. B. (2012a). Neuropsychological performance in survivors of breast cancer more than 20 years after adjuvant chemotherapy. Journal of Clinical Oncology, 30(10), 1080–1086. doi:10.1200/JCO.2011.37.0189.PubMedCrossRefGoogle Scholar
  25. Koppelmans, V., de Ruiter, M. B., van der Lijn, F., Boogerd, W., Seynaeve, C., van der Lugt, A., et al. (2012b). Global and focal brain volume in long-term breast cancer survivors exposed to adjuvant chemotherapy. [Research Support, Non-U.S. Gov’t]. Breast Cancer Research and Treatment, 132(3), 1099–1106. doi:10.1007/s10549-011-1888-1.PubMedCrossRefGoogle Scholar
  26. Koppelmans, V., Groot, M. D., de Ruiter, M. B., Boogerd, W., Seynaeve, C., Vernooij, M. W., et al. (2012c). Global and focal white matter integrity in breast cancer survivors 20 years after adjuvant chemotherapy. Human Brain Mapping. doi:10.1002/hbm.22221.PubMedGoogle Scholar
  27. Kreukels, B. P., Hamburger, H. L., de Ruiter, M. B., van Dam, F. S., Ridderinkhof, K. R., Boogerd, W., et al. (2008). ERP amplitude and latency in breast cancer survivors treated with adjuvant chemotherapy. [Clinical Trial Research Support, Non-U.S. Gov’t]. Clinical Neurophysiology, 119(3), 533–541. doi:10.1016/j.clinph.2007.11.011.PubMedCrossRefGoogle Scholar
  28. Kreukels, B. P., Schagen, S. B., Ridderinkhof, K. R., Boogerd, W., Hamburger, H. L., Muller, M. J., et al. (2006). Effects of high-dose and conventional-dose adjuvant chemotherapy on long-term cognitive sequelae in patients with breast cancer: an electrophysiologic study. [Comparative Study Research Support, Non-U.S. Gov’t]. Clinical Breast Cancer, 7(1), 67–78. doi:10.3816/CBC.2006.n.015.PubMedCrossRefGoogle Scholar
  29. Kreukels, B. P., Schagen, S. B., Ridderinkhof, K. R., Boogerd, W., Hamburger, H. L., & van Dam, F. S. (2005). Electrophysiological correlates of information processing in breast-cancer patients treated with adjuvant chemotherapy. [Research Support, Non-U.S. Gov’t]. Breast Cancer Research and Treatment, 94(1), 53–61. doi:10.1007/s10549-005-7093-3.PubMedCrossRefGoogle Scholar
  30. McAllister, T. W., Saykin, A. J., Flashman, L. A., Sparling, M. B., Johnson, S. C., Guerin, S. J., et al. (1999). Brain activation during working memory 1 month after mild traumatic brain injury: a functional MRI study. [Clinical Trial Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, P.H.S.]. Neurology, 53(6), 1300–1308.PubMedCrossRefGoogle Scholar
  31. McAllister, T. W., Sparling, M. B., Flashman, L. A., Guerin, S. J., Mamourian, A. C., & Saykin, A. J. (2001). Differential working memory load effects after mild traumatic brain injury. [Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, P.H.S.]. NeuroImage, 14(5), 1004–1012. doi:10.1006/nimg.2001.0899.PubMedCrossRefGoogle Scholar
  32. 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. [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t]. Breast Cancer Research and Treatment, 123(3), 819–828. doi:10.1007/s10549-010-1088-4.PubMedCentralPubMedCrossRefGoogle Scholar
  33. McDonald, B. C., Conroy, S. K., Ahles, T. A., West, J. D., & 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. [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t]. Journal of Clinical Oncology, 30(20), 2500–2508. doi:10.1200/JCO.2011.38.5674.PubMedCrossRefGoogle Scholar
  34. McDonald, B. C., Conroy, S. K., Smith, D. J., West, J. D., & Saykin, A. J. (2012b). Frontal gray matter reduction after breast cancer chemotherapy and association with executive symptoms: a replication and extension study. Brain, Behavior, and Immunity. doi:10.1016/j.bbi.2012.05.007.PubMedGoogle Scholar
  35. Menon, V., Boyett-Anderson, J. M., Schatzberg, A. F., & Reiss, A. L. (2002). Relating semantic and episodic memory systems. [Clinical Trial Research Support, U.S. Gov’t, P.H.S.]. Brain Research. Cognitive Brain Research, 13(2), 261–265.PubMedCrossRefGoogle Scholar
  36. Minisini, A., Atalay, G., Bottomley, A., Puglisi, F., Piccart, M., & Biganzoli, L. (2004). What is the effect of systemic anticancer treatment on cognitive function? The Lancet Oncology, 5(5), 273–282. doi:10.1016/s1470-2045(04)01465-2.PubMedCrossRefGoogle Scholar
  37. Monk, T. G., Weldon, B. C., Garvan, C. W., Dede, D. E., van der Aa, M. T., Heilman, K. M., et al. (2008). Predictors of cognitive dysfunction after major noncardiac surgery. [Comparative Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t]. Anesthesiology, 108(1), 18–30. doi:10.1097/01.anes.0000296071.19434.1e.PubMedCrossRefGoogle Scholar
  38. Nelson, W. L., & Suls, J. (2013). New approaches to understand cognitive changes associated with chemotherapy for non-central nervous system tumors. Journal of Pain and Symptom Management. doi:10.1016/j.jpainsymman.2012.11.005.Google Scholar
  39. Nguyen, A., Geist, C., Ganz, P. A., L., K., Castellon, S. A., Irwin, M., et al. (2012). Effects of adjuvant therapy on cerebral function during short-term and long-term memory tasks. The Journal of Nuclear Medicine, 53 (Supplemental 1)(Abstract No.1956).Google Scholar
  40. Perry, A., & Schmidt, R. E. (2006). Cancer therapy-associated CNS neuropathology: an update and review of the literature. [Review]. Acta Neuropathologica, 111(3), 197–212. doi:10.1007/s00401-005-0023-y.PubMedCrossRefGoogle Scholar
  41. Pomykala, K. L., & Silverman, D. H. S. (2012). Alterations in brain structure and function after chemotherapy for cancer. Future Neurology, 7(4), 443–452.CrossRefGoogle Scholar
  42. Price, C. C., Garvan, C. W., & Monk, T. G. (2008). Type and severity of cognitive decline in older adults after noncardiac surgery. [Comparative Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t]. Anesthesiology, 108(1), 8–17. doi:10.1097/01.anes.0000296072.02527.18.PubMedCentralPubMedCrossRefGoogle Scholar
  43. Roth, R. M., Isquith, P. K., & Gioia, G. A. (2005). BRIEF-A behavior rating inventory of executive function-adult version professional manual. Lutz: Psychological Assessment Resources.Google Scholar
  44. Saykin, A. J., Wishart, H. A., Rabin, L. A., Flashman, L. A., McHugh, T. L., Mamourian, A. C., et al. (2004). Cholinergic enhancement of frontal lobe activity in mild cognitive impairment. [Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, Non-P.H.S. Research Support, U.S. Gov’t, P.H.S.]. Brain, 127(Pt 7), 1574–1583. doi:10.1093/brain/awh177.PubMedCrossRefGoogle Scholar
  45. Schagen, S. B., Hamburger, H. L., Muller, M. J., Boogerd, W., & van Dam, F. S. (2001). Neurophysiological evaluation of late effects of adjuvant high-dose chemotherapy on cognitive function. [Clinical Trial Comparative Study Multicenter Study Randomized Controlled Trial]. Journal of Neuro-Oncology, 51(2), 159–165.PubMedCrossRefGoogle Scholar
  46. Scherling, C., Collins, B., Mackenzie, J., Bielajew, C., & Smith, A. (2011). Pre-chemotherapy differences in visuospatial working memory in breast cancer patients compared to controls: an FMRI study. Frontiers in Human Neuroscience, 5, 122. doi:10.3389/fnhum.2011.00122.PubMedCentralPubMedCrossRefGoogle Scholar
  47. Scherling, C., Collins, B., Mackenzie, J., Bielajew, C., & Smith, A. (2012a). Prechemotherapy differences in response inhibition in breast cancer patients compared to controls: a functional magnetic resonance imaging study. [Research Support, Non-U.S. Gov’t]. Journal of Clinical and Experimental Neuropsychology, 34(5), 543–560. doi:10.1080/13803395.2012.666227.CrossRefGoogle Scholar
  48. Scherling, C., Collins, B., Mackenzie, J., Lepage, C., Bielajew, C., & Smith, A. (2012b). Structural brain differences in breast cancer patients compared to matched controls prior to chemotherapy. International Journal of Biology, 4(2), 3–25. doi:10.5539/ijb.v4n2p3.Google Scholar
  49. Seruga, B., Zhang, H., Bernstein, L. J., & Tannock, I. F. (2008). Cytokines and their relationship to the symptoms and outcome of cancer. [10.1038/nrc2507]. Nature Reviews. Cancer, 8(11), 887–899.PubMedCrossRefGoogle Scholar
  50. Silverman, D. H., Dy, C. J., Castellon, S. A., Lai, J., Pio, B. S., Abraham, L., et al. (2007). Altered frontocortical, cerebellar, and basal ganglia activity in adjuvant-treated breast cancer survivors 5–10 years after chemotherapy. [Research Support, Non-U.S. Gov’t]. Breast Cancer Research and Treatment, 103(3), 303–311. doi:10.1007/s10549-006-9380-z.PubMedCrossRefGoogle Scholar
  51. Taillibert, S., Voillery, D., & Bernard-Marty, C. (2007). Chemobrain: is systemic chemotherapy neurotoxic? [Review]. Current Opinion in Oncology, 19(6), 623–627. doi:10.1097/CCO.0b013e3282f0e224.PubMedCrossRefGoogle Scholar
  52. van Dam, F. S., Schagen, S. B., Muller, M. J., Boogerd, W., vd Wall, E., Droogleever Fortuyn, M. E., et al. (1998). Impairment of cognitive function in women receiving adjuvant treatment for high-risk breast cancer: high-dose versus standard-dose chemotherapy. [Clinical Trial Randomized Controlled Trial]. Journal of the National Cancer Institute, 90(3), 210–218.PubMedCrossRefGoogle Scholar
  53. Vardy, J., Booth, C., Pond, G. R., Zhan, H., Galica, J., Dhillon, H., et al. (2007). Cytokine levels in patients with colorectal cancer and breast cancer and their relationship to fatigue and cognitive function. Chicago: Abstract Presented at the American Society of Clinical Oncology- Poster, Patient and Survivor Care. 9070.Google Scholar
  54. Videnovic, A., Semenov, I., Chua-Adajar, R., Baddi, L., Blumenthal, D. T., Beck, A. C., et al. (2005). Capecitabine-induced multifocal leukoencephalopathy: a report of five cases. [Case Reports]. Neurology, 65(11), 1792–1794. doi:10.1212/01.wnl.0000187313.83515.7e. discussion 1685.PubMedCrossRefGoogle Scholar
  55. Wager, T. D., & Smith, E. E. (2003). Neuroimaging studies of working memory: a meta-analysis. [Meta-Analysis Research Support, U.S. Gov’t, Non-P.H.S. Research Support, U.S. Gov’t, P.H.S. Review]. Cognitive, Affective, & Behavioral Neuroscience, 3(4), 255–274.CrossRefGoogle Scholar
  56. Wefel, J. S., Kayl, A. E., & Meyers, C. A. (2004). Neuropsychological dysfunction associated with cancer and cancer therapies: a conceptual review of an emerging target. [Review]. British Journal of Cancer, 90(9), 1691–1696. doi:10.1038/sj.bjc.6601772.PubMedCentralPubMedGoogle Scholar
  57. Wefel, J. S., & Schagen, S. B. (2012). Chemotherapy-related cognitive dysfunction. Current Neurology and Neuroscience Reports, 12(3), 267–275. doi:10.1007/s11910-012-0264-9.PubMedCrossRefGoogle Scholar
  58. Wishart, H. A., Saykin, A. J., McDonald, B. C., Mamourian, A. C., Flashman, L. A., Schuschu, K. R., et al. (2004). Brain activation patterns associated with working memory in relapsing-remitting MS. [Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, Non-P.H.S. Research Support, U.S. Gov’t, P.H.S.]. Neurology, 62(2), 234–238.PubMedCrossRefGoogle Scholar
  59. Yoshikawa, E., Matsuoka, Y., Inagaki, M., Nakano, T., Akechi, T., Kobayakawa, M., et al. (2005). No adverse effects of adjuvant chemotherapy on hippocampal volumein Japanese breast cancer survivors. Breast Cancer Research and Treatment, 92(1), 81–84. doi:10.1007/s10549-005-1412-6.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • K. L. Pomykala
    • 1
  • M. B. de Ruiter
    • 2
  • S. Deprez
    • 3
  • B. C. McDonald
    • 4
  • D. H. S. Silverman
    • 1
    • 5
  1. 1.Ahmanson Translational Imaging Division, Department of Molecular & Medical Pharmacology, David Geffen School of MedicineUniversity of CaliforniaLos AngelesUSA
  2. 2.Department of Psychosocial Research and EpidemiologyNetherlands Cancer InstituteAmsterdamThe Netherlands
  3. 3.Department of RadiologyUniversity Hospital Gasthuisberg, Katholieke Universiteit LeuvenLeuvenBelgium
  4. 4.Center for Neuroimaging, Melvin and Bren Simon Cancer CenterIndiana University School of MedicineIndianapolisUSA
  5. 5.Department of Molecular and Medical PharmacologyDavid Geffen School of Medicine at UCLALos AngelesUSA

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