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Candidate mechanisms for chemotherapy-induced cognitive changes

Key Points

  • Evidence for chemotherapy-induced cognitive changes comes from studies that have used neuropsychological testing, imaging (structural and functional magnetic resonance imaging (MRI) and positron emission tomography (PET)) and electrophysiological (electroencephalogram) assessments. Emerging data from animal studies also support the effect of chemotherapy on cognitive function.

  • Most chemotherapy agents administered systemically do not cross the blood–brain barrier in significant doses; however, the amount that enters the brain can be modified by genetic variability in blood–brain barrier transporters. In addition, recent data from animal studies suggest that very small doses of common chemotherapy agents can cause cell death and reduced cell division in brain structures crucial for cognition, even at doses that do not effectively kill tumour cells.

  • Chemotherapy might cause cognitive changes through DNA damage caused directly by the cytotoxic agents or through increases in oxidative stress. Many chemotherapeutic agents also cause the shortening of telomeres, thereby accelerating cell ageing. Genetic variability in DNA-repair genes might influence the extent of, and recovery from, chemotherapy-associated DNA damage.

  • Chemotherapy-induced cognitive changes might also be related to the neurotoxic effects of cytokine deregulation. Cytokine deregulation and inflammation can also lead to increased oxidative stress, which could establish a cycle of increased DNA damage that triggers additional cytokine release.

  • Variability in genes that regulate neural repair and/or plasticity, such as apolipoprotein E (APOE) and brain-derived neurotrophic factor (BDNF), and neurotransmission, such as catechol-O-methyltransferase (COMT), might increase the vulnerability of an individual to chemotherapy-induced cognitive changes.

  • Changes in levels of oestrogen and testosterone are associated with cognitive decline, and can be influenced by chemotherapy (for example, chemotherapy-induced menopause) or hormonal treatments, such as tamoxifen or aromatase inhibitors for breast cancer or androgen ablation for prostate cancer.

  • The effects of chemotherapy-associated cardiovascular toxicity and alterations in neuroendocrine function on cognitive function require investigation.

Abstract

The mechanism(s) for chemotherapy-induced cognitive changes are largely unknown; however, several candidate mechanisms have been identified. We suggest that shared genetic risk factors for the development of cancer and cognitive problems, including low-efficiency efflux pumps, deficits in DNA-repair mechanisms and/or a deregulated immune response, coupled with the effect of chemotherapy on these systems, might contribute to cognitive decline in patients after chemotherapy. Furthermore, the genetically modulated reduction of capacity for neural repair and neurotransmitter activity, as well as reduced antioxidant capacity associated with treatment-induced reduction in oestrogen and testosterone levels, might interact with these mechanisms and/or have independent effects on cognitive function.

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Figure 1: Neuroimaging methods relevant to the assessment of cognitive changes.
Figure 2: Candidate mechanisms.

References

  1. 1

    Silberfarb, P. M. Chemotherapy and cognitive defects in cancer patients. Annu. Rev. Med. 34, 35–46 (1983).

    CAS  PubMed  Article  Google Scholar 

  2. 2

    Wieneke, M. H. & Dienst, E. R. Neuropsychological assessment of cognitive functioning following chemotherapy for breast cancer. Psychooncology 4, 61–66 (1995).

    Article  Google Scholar 

  3. 3

    van Dam, F. S. et al. Impairment of cognitive function in women receiving adjuvant treatment for high-risk breast cancer: high-dose versus standard-dose chemotherapy. [comment]. J. Natl Cancer Inst. 90, 210–218 (1998).

    CAS  PubMed  Article  Google Scholar 

  4. 4

    Schagen, S. B. et al. Cognitive deficits after postoperative adjuvant chemotherapy for breast carcinoma. Cancer 85, 640–650 (1999).

    CAS  PubMed  Article  Google Scholar 

  5. 5

    Brezden, C. B. et al. Cognitive function in breast cancer patients receiving adjuvant chemotherapy. J. Clin. Oncol. 18, 2695–2701 (2000).

    CAS  PubMed  Article  Google Scholar 

  6. 6

    Ahles, T. A. et al. Neuropsychological impact of standard-dose chemotherapy in long-term survivors of breast cancer and lymphoma. J. Clin. Oncol. 20, 485–493 (2002).

    CAS  PubMed  Article  Google Scholar 

  7. 7

    Tchen, M. et al. Cognitive function, fatigue, and menopausal symptoms in women receiving adjuvant chemotherapy for breast cancer. J. Clin. Oncol. 21, 4175–4183 (2003).

    PubMed  Article  Google Scholar 

  8. 8

    Castellon, S. A. et al. Neurocognitive performance in breast cancer survivors exposed to adjuvant chemotherapy and tamoxifen. J. Clin. Exp. Neuropsychol. 26, 955–969 (2004).

    PubMed  Article  Google Scholar 

  9. 9

    Wefel, J. S. et al. The cognitive sequelae of standard-dose adjuvant chemotherapy in women with breast carcinoma: results of a prospective, randomized, longitudinal trial. Cancer 100, 2292–2299 (2004).

    CAS  PubMed  Article  Google Scholar 

  10. 10

    Schilling, V. et al. The effects of adjuvant chemotherapy on cognition in women with breast cancer — preliminary results of an observational study. The Breast 14, 142–150 (2005).

    Article  Google Scholar 

  11. 11

    Jenkins, V. et al. A 3-year prospective study of the effects of adjuvant treatments on cognition in women with early stage breast cancer. Br. J. Cancer 94, 828–834 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. 12

    Donovan, K. A. et al. Cognitive functioning after adjuvant chemotherapy and/or radiotherapy for early stage breast carcinoma. Cancer 104, 2499–2507 (2005).

    PubMed  PubMed Central  Article  Google Scholar 

  13. 13

    Tannock, I. F., Ahles, T. A., Ganz, P. A. & van Dam, F. S. Cognitive impairment associated with chemotherapy for cancer: report of a workshop. J. Clin. Oncol. 22, 2233–2239 (2004). This paper provides an overview of a consensus conference that included most of the researchers from around the world who were conducting research on chemotherapy-induced cognitive changes.

    PubMed  Article  Google Scholar 

  14. 14

    Ahles, T. A. & Saykin, A. J. Breast cancer chemotherapy-related cognitive dysfunction. Clin. Breast Cancer Suppl. 3, S84–S90 (2002).

  15. 15

    Ferguson, R. J. & Ahles, T. A. Low neuropsychologic performance among adult cancer survivors treated with chemotherapy. Curr. Neurol. Neurosci. Rep. 3, 215–222 (2003).

    PubMed  Article  Google Scholar 

  16. 16

    Anderson-Hanley, C., Sherman, M. L., Riggs, R. Agocha, V. V. & Compas, B. E. Neuropsychological effects of treatments for adults with cancer: A meta-analysis and review of the literature. J. Int. Neuropsychol. Soc. 9, 967–982 (2003).

    PubMed  Article  Google Scholar 

  17. 17

    Saykin, A. J., Ahles, T. A. & McDonald, B. C. Mechanisms of chemotherapy-induced cognitive disorders: neuropsychological, pathophysiological and neuroimaging perspectives. Sem. Clin. Neuropsych. 8, 201–216 (2003).

    Article  Google Scholar 

  18. 18

    Stemmer, S. et al. White matter changes in patients with breast cancer treated with high-dose chemotherapy and autologous bone marrow support. Am. J. Neuroradiol. 15, 1267–1273 (1994).

    CAS  PubMed  Google Scholar 

  19. 19

    Saykin, A. J. et al. Altered brain activation following systemic chemotherapy for breast cancer: interim analysis from a prospective study. J. Int. Neuropsychol. Soc. 12, 131 (2006).

    Google Scholar 

  20. 20

    Kreukels, B. P. et al. Electrophysiological correlates of information processing in breast-cancer patients treated with chemotherapy. Breast Cancer Res. Treat. 94, 53–61 (2005).

    CAS  PubMed  Article  Google Scholar 

  21. 21

    Kreukels, B. P. et al. Effects of high-dose and conventional-dose adjuvant chemotherapy on long-term cognitive sequelae in patients with breast cancer: an electrophysiologic study. Clin. Breast Cancer 7, 67–78 (2006).

    CAS  PubMed  Article  Google Scholar 

  22. 22

    Wefel, J. S. et al. Chemobrain in breast carcinoma? A prologue. Cancer 101, 466–475 (2004).

    PubMed  Article  Google Scholar 

  23. 23

    Meyers, C. A., Albitar M. & Estey, E. Cognitive impairment, fatigue, and cytokine levels in patients with acute myelogenous leukemia or myelodysplastic syndrome. Cancer 104, 788–793 (2005).

    CAS  PubMed  Article  Google Scholar 

  24. 24

    Ahles, T. A. et al. Psychological and neuropsychological functioning of patients with limited small-cell lung cancer treated with chemotherapy and radiation therapy with or without warfarin, a study for Cancer and Leukemia Group B. J. Clin. Oncol. 16, 1954–1960 (1998).

    CAS  PubMed  Article  Google Scholar 

  25. 25

    Wagner, L. I. et al. Trajectory of cognitive impairment during breast cancer treatment: a prospective analysis. J. Clin. Oncol. Suppl. 24, 8500 (2006).

    Google Scholar 

  26. 26

    Heflin, L. H. et al. Cancer as a risk factor for long-term cognitive deficits and dementia. J. Natl Cancer Inst. 97, 854–856 (2005).

    PubMed  Article  Google Scholar 

  27. 27

    Verstappen C. C. P., Heimans, J. J., Hoekman, K. & Postma T. J. Neurotoxic complications of chemotherapy in patients with cancer: Clinical signs and optimal management. Drugs 63, 1549–1563 (2003).

    CAS  PubMed  Article  Google Scholar 

  28. 28

    Troy, L. et al. Cisplatin-based therapy: A neurological and neuropsychological review. Psychooncology 9, 29–39 (2000).

    CAS  PubMed  Article  Google Scholar 

  29. 29

    Ginos J. Z. et al. [13N]cisplatin PET to assess pharmacokinetics of intro-arterial versus intravenous chemotherapy for malignant brain tumors. J. Nucl. Med. 28, 1844–1852 (1987).

    CAS  PubMed  Google Scholar 

  30. 30

    Mitsuki, S. et al. Pharmacokinetics of 11C-labelled BCNU and SARCNU in gliomas studied by PET. J.Neurooncol. 10, 47–55 (1991).

    CAS  PubMed  Article  Google Scholar 

  31. 31

    Gangloff, A. et al. Estimation of paclitaxel biodistribution and uptake in human-derived xenografts in vivo with 18F-Fluoropaclitaxel. J. Nucl. Med. 46, 1866–1871 (2005).

    CAS  PubMed  Google Scholar 

  32. 32

    Dietrich, J., Han, R., Yang, Y., Mayer-Proschel, M. & Noble, M. CNS progenitor cells and oligodendrocytes are targets of chemotherapeutic agents in vitro and in vivo. J. Biol. 5, 22 [Epub ahead of print] (2006). This is an excellent paper describing in vitro and in vivo (mice) studies showing that common chemotherapy agents caused increased cell death and decreased cell division in the subventricular zone and in the dentate gyrus of the hippocampus, and in the corpus callosum. These effects were seen with doses that were not effective in causing cell death in tumor cell lines.

    PubMed  PubMed Central  Article  Google Scholar 

  33. 33

    Jamroziak, K. & Robak, T. Pharmacogenomics of MDR1/ABCB1 gene: the influence on risk and clinical outcome of haematological malignancies. Hematology 9, 91–105 (2004).

    CAS  PubMed  Article  Google Scholar 

  34. 34

    Hoffmeyer, S. et al. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc. Natl Acad. Sci. USA 97, 3473–3478 (2000).

    CAS  PubMed  Article  Google Scholar 

  35. 35

    Kreb, R. Implications of genetic polymorphisms in drug transporters for pharmacotherapy. Cancer Lett. 234, 4–33 (2006). This manuscript describes evidence for genetic variability in drug transporters and their influence on drug disposition and clinical response.

    Article  CAS  Google Scholar 

  36. 36

    Muramatsu, T. et al. Age-related differences in vincristine toxicity and biodistribution in wild-type and transporter-deficient mice. Oncol. Res. 14, 331–343 (2004).

    CAS  PubMed  Article  Google Scholar 

  37. 37

    Uhr, M., Holsboer, F. & Muller, M. B. Penetration of endogenous steroid hormones corticosterone, cortisol, aldosterone and progesterone into the brain is enhanced in mice deficient for both mdr1a and mdr1b p-glycoproteins. J. Neuroendocrinol. 14, 753–759 (2002).

    CAS  PubMed  Article  Google Scholar 

  38. 38

    Rolig, R. L. & McKinnon, P. J. Linking DNA damage and neurodegeneration. Trends Neurosci. 23, 417–424 (2000). This paper provides an overview of the evidence linking DNA damage to neurodegeneration and cognitive function.

    CAS  PubMed  Article  Google Scholar 

  39. 39

    Goode, E. L., Ulrich, C. M. & Potter, J. D. Polymorphisms in DNA repair genes and associations with cancer risk. Cancer Epidemiol. Biomarkers Prev. 11, 1513–1530 (2002).

    CAS  PubMed  Google Scholar 

  40. 40

    Caldecott, K. W. DNA single-strand breaks and neurodegeneration. DNA Repair 3, 875–882 (2004).

    CAS  PubMed  Article  Google Scholar 

  41. 41

    Abner, C. W. & McKinnon, P. J. The DNA double-strand break response in the nervous system. DNA Repair 3, 1141–1147 (2004).

    CAS  PubMed  Article  Google Scholar 

  42. 42

    Fishel, M. L., Vasko, M. R. & Kelley, M. R. DNA repair in neurons: so if they don't divide what's to repair? Mutat. Res. 614, 24–36 (2007). This paper reviews the relevance of DNA-repair pathways to DNA damage in post-mitotic neurons, and the impact of DNA damage on neuronal survival and brain ageing. Additionally, these authors relate DNA repair to neurotoxicity associated with chemotherapy, including cognitive side effects and peripheral neuropathy.

    CAS  PubMed  Article  Google Scholar 

  43. 43

    Sedletska, Y., Giraud-Panis, M.-J. & Malinge, J.-M. Cisplatin is a DNA-damaging antitumour coumpound triggering multifactorial biochemical responses in cancer cells: Importance of apoptotic pathways. Curr. Med. Chem. Anticancer Agents 5, 251–265 (2005).

    CAS  PubMed  Article  Google Scholar 

  44. 44

    Blasiak J. et al. Basal, oxidative and alkylative DNA damage, DNA repair efficacy and mutagen sensitivity in breast cancer. Mutat. Res. 554, 139–148 (2004). Using the comet assay, these investigators showed greater DNA damage and lower DNA repair efficacy in patients with breast cancer, both before and after chemotherapy.

    CAS  PubMed  Article  Google Scholar 

  45. 45

    Nadin S. B., Vargas-Roig, L. M., Drago, G., Ibarra, J. & Ciocca, D. R. DNA damage and repair in peripheral blood lymphocytes from healthy individuals and cancer patients: a pilot study on the implications in response to chemotherapy. Cancer Lett. 239, 84–87 (2006).

    CAS  PubMed  Article  Google Scholar 

  46. 46

    Wardell, T. M. et al. Changes in human mitochondrial genome after treatment of malignant disease. Mutat. Res. 525, 19–27 (2003).

    CAS  PubMed  Article  Google Scholar 

  47. 47

    Weijl, N. I. et al. Non-protein bound iron release during chemotherapy in cancer patients. Clin. Sci. 106, 475–484 (2004).

    CAS  PubMed  Article  Google Scholar 

  48. 48

    Kaya, E. et al. Oxidant/antioxidant parameters and their relationship with chemotherapy in Hodgkin's lymphoma. J. Int. Med. Res. 33, 687–692 (2005).

    CAS  PubMed  Article  Google Scholar 

  49. 49

    Papageorgiou, M. et al. Cancer chemotherapy reduces plasma total antioxidant capacity in children with malignancies. Leukemia Res. 29, 11–16 (2005).

    CAS  Article  Google Scholar 

  50. 50

    Kennedy, D. D., Ladas, E. J., Rheingold, S. R., Blumberg, J. & Kelly, K. M. Antioxidant status decreases in children with acute lymphoblastic leukemia during the first six months of chemotherapy treatment. Ped. Blood Cancer 44, 378–385 (2005).

    Article  Google Scholar 

  51. 51

    Mariani, E., Polidori, M. C., Cherubini, A. & Mecocci, P. Oxidative stress in brain aging, neurodegenerative and vascular diseases: an overview. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 827, 65–75 (2005).

    CAS  PubMed  Article  Google Scholar 

  52. 52

    Migliore, L. et al. Oxidative DNA damage in peripheral leukocytes of mild cognitive impairment and AD patients. Neurobiol. Aging 26, 567–573 (2005). The results of this study showed that patients with mild cognitive impairment, a condition characterized by a relatively isolated impairment in memory in the context of normal functioning in other areas, had higher levels of DNA damage compared with older adults without mild cognitive impairment.

    CAS  PubMed  Article  Google Scholar 

  53. 53

    Keller, J. N. et al. Evidence of increased oxidative damage in subjects with mild cognitive impairment. Neurology 64, 1152–1156 (2005). This study showed that patients who had been diagnosed with mild cognitive impairment had elevated levels of DNA damage in the brain at autopsy, suggesting a relationship between DNA damage seen peripherally in this population and DNA damage in the CNS.

    CAS  PubMed  Article  Google Scholar 

  54. 54

    Harrison, J. F. et al. Oxidative stress-induced apoptosis in neurons correlates with mitcochondrial DNA base exicision repair pathway imbalance. Nucleic Acids Res. 33, 4660–4671 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. 55

    Vajdovich, P. et al. Redox status in dogs with non-hodgkin lymphomas. An ESR study. Cancer Lett. 224, 339–346 (2005).

    CAS  PubMed  Article  Google Scholar 

  56. 56

    Hung, R., Hall, J., Brennan, P. & Boffetta, P. Genetic polymorphisms in the base excision repair pathway and cancer risk: A HuGE review. Am. J. Epidemiol. 162, 925–942 (2005).

    PubMed  Article  Google Scholar 

  57. 57

    von Zglinicki, T. & Martin-Ruiz, C. M. Telomeres as biomarkers for ageing and age-related diseases. Curr. Mol. Med. 5, 197–203 (2005).

    CAS  PubMed  Article  Google Scholar 

  58. 58

    Vasa-Nicotera, M. et al. Mapping of a major locus that determines telomere length in humans. Am. J. Hum. Genet. 76, 147–151 (2005).

    CAS  PubMed  Article  Google Scholar 

  59. 59

    Schroder, C. P. et al. Telomere length in breast cancer patients before and after chemotherapy with or without stem cell transplation. Br. J. Cancer 84, 1348–1353 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. 60

    Lahav, M. et al. Nonmyeloablative conditioning does not prevent telomere shortening after allogeneic stem cell transplantation. Transplantation 80, 969–976 (2005).

    PubMed  Article  Google Scholar 

  61. 61

    Maccormick, R. E. Possible acceleration of aging by adjuvant chemotherapy: a cause of early onset frailty? Med. Hypotheses 67, 212–215 (2006). This manuscript reviews the evidence that morbidity associated with chemotherapy might be related to acceleration of the ageing process.

    CAS  PubMed  Article  Google Scholar 

  62. 62

    Flanary, B. E. & Streit, W. J. Progressive telomere shortening occurs in cultured rat microglia, but not astrocytes. Glia 45, 75–88 (2004).

    PubMed  Article  Google Scholar 

  63. 63

    Wilson, C. J., Finch, C. E. & Cohen H. J. Cytokines and cognition — the case for head-to-toe inflammatory paradigm. J. Am. Geriatr. Soc. 50, 2041–2056 (2002).

    PubMed  Article  Google Scholar 

  64. 64

    Tonelli, L. H., Postolache, T. T. & Sternberg, E. M. Inflammatory genes and neural activity: involvement of immune genes in synaptic function and behavior. Front. Biosci. 10, 675–680 (2005).

    CAS  PubMed  Article  Google Scholar 

  65. 65

    Cleeland, C. S. et al. Are the symptoms of cancer and cancer treatment due to a shared biologic mechanism? A cytokine-immunologic model of cancer symptoms. Cancer 97, 2919–2925 (2003).

    PubMed  Article  Google Scholar 

  66. 66

    Kelley, K. W. et al. Cytokine-induced sickness behavior. Brain Behav. Immun. 17, S112–S118 (2003)

    CAS  PubMed  Article  Google Scholar 

  67. 67

    Maier, S. F. & Watkins L. R. Immune-to-central nervous system communication and its role in modulating pain and cognition: Implications for cancer and cancer treatments. Brain Behav. Immun. 17, S125–S131 (2003).

    CAS  PubMed  Article  Google Scholar 

  68. 68

    Reichenberg, A. et al. Cytokine-associated emotional and cognitive disturbances in humans. Arch. Gen. Psych. 58, 445–452 (2001).

    CAS  Article  Google Scholar 

  69. 69

    Krabbe, K. S. et al. Low-dose endotoxemia and human neuropsychological functions. Brain Behav. Immun. 19, 453–460 (2005).

    CAS  PubMed  Article  Google Scholar 

  70. 70

    Trask, P. C., Esper, P., Riba, M. & Redman, B. Psychiatric side effects of interferon therapy: prevalence, proposed mechanisms, and future directions. J. Clin. Oncol. 18, 2316–2326 (2000).

    CAS  PubMed  Article  Google Scholar 

  71. 71

    Scheibel, R. S., Valentine, A. D., O'Brien, S. & Meyers, C. A. Cognitive dysfunction and depression during treatment with interferon-α and chemotherapy. J.Neuropsych. Clin. Neurosci. 16, 185–191 (2004).

    CAS  Article  Google Scholar 

  72. 72

    Capuron, L., Ravaud, A. & Dantzer, R. Timing and specificity of the cognitive changes induced by interleukin-2 and interferon-α treatments in cancer patients. Psychosom. Med. 63, 376–386 (2001).

    CAS  PubMed  Article  Google Scholar 

  73. 73

    Tsavaris, N., Kosmas, C., Vadiaka, M., Kanelopoulos, P. & Boulamatsis, D. Immune changes in patients with advanced breast cancer undergoing chemotherapy with taxanes. Br. J. Cancer 87, 21–27 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. 74

    Pusztai, L. et al. Changes in plasma levels of inflammatory cytokines in response to paclitaxel chemotherapy. Cytokine 25, 94–102 (2004).

    CAS  PubMed  Article  Google Scholar 

  75. 75

    Penson, R. T. et al. Chtokines IL-1β, IL-2, IL-6, IL-8, MCP-1, GM-CSF and TNFα in patients with epithelial ovarian cancer and their relationship to treatment with paclitaxel. Int. J. Gynecol. Cancer 10, 33–41 (2000).

    PubMed  Article  Google Scholar 

  76. 76

    Callado-Hidalgo, A., Bower, J. E., Ganz, P. A., Cole, S. W. & Irwin, M. R. Inflammatory biomarkers for persistent fatigue in breast cancer survivors. Clin. Cancer Res. 12, 2759–2766

  77. 77

    Bower, J. E., Ganz, P. A., Aziz, N., Fahey, J. L. Fatigue and proinflammatory cytokine activity in breast cancer survivors. Psychosom. Med. 64, 604–611 (2002).

    PubMed  Article  Google Scholar 

  78. 78

    Balkwill, F. & Mantovani, A. Inflammation and cancer: back to Virchow? Lancet 357, 539–545 (2001).

    CAS  Article  Google Scholar 

  79. 79

    de Visser, K. E., Eichten, A. & Coussens, L. M. Paradoxical roles of the immune system during cancer development. Nature Rev. Cancer 6, 24–37 (2006). This paper presents evidence in support of a role for chronic inflammation in enhancing the predisposition to develop cancer. Furthermore, the authors present evidence that genetic polymorphisms that regulate immune function can affect cancer risk.

    CAS  Article  Google Scholar 

  80. 80

    McGeer, P. L. & McGeer, E. G. Polymorphisms in inflammatory genes and risk of Alzheimer Disease. Arch. Neurol. 58, 1790–1792 (2001).

    CAS  PubMed  Article  Google Scholar 

  81. 81

    Morley, K. I. & Montgomery, G. W. The genetics of cognitive processes: candidate genes in humans and animals. Behav. Genet. 31, 511–531 (2001).

    CAS  PubMed  Article  Google Scholar 

  82. 82

    Chen, Y. et al. Motor and cognitive deficits in apolipoprotein E-deficient mice after closed head injury. Neuroscience 80, 1255–1262 (1997).

    CAS  PubMed  Article  Google Scholar 

  83. 83

    Hartman, R. E. et al. Apolipoprotein E4 influences amyloid deposition but not cell loss after traumatic brain injury in a mouse model of Alzheimer's disease. J. Neurosci. 22, 10083–10087 (2002).

    CAS  PubMed  Article  Google Scholar 

  84. 84

    Sabo, T. et al. Susceptibility of transgenic mice expressing human apolipoprotein E to closed head injury: the allele E3 is neuroprotective whereas E4 increases fatalities. Neuroscience 101, 879–884 (2000).

    CAS  PubMed  Article  Google Scholar 

  85. 85

    Laws, S. M. et al. APOE-epsilon4 and APOE-491A polymorphisms in individuals with subjective memory loss. Mol. Psych. 7, 768–775 (2002).

    CAS  Article  Google Scholar 

  86. 86

    Nathoo, N. et al. Genetic vulnerability following traumatic brain injury: the role of apolipoprotein E. Mol. Pathol. 56, 132–136 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  87. 87

    Ahles, T. A., Saykin, A. J. & Noll, W. W. et al. The relationship of APOE genotype to neuropsychological performance in long-term cancer survivors treated with standard dose chemotherapy. Psychooncology 12, 612–619 (2003) This is the first study to show an association between APOE genotype and cognitive functioning in long-term cancer survivors.

    PubMed  Article  Google Scholar 

  88. 88

    Lind, J. et al. Reduced hippocampal volume in non-demented carriers of the apolipoprotein E ɛ4: relation to chronological age and recognition memory. Neurosci. Lett. 396, 23–27 (2006).

    CAS  PubMed  Article  Google Scholar 

  89. 89

    Pang, P. T. & Lu, B. Regulation of late-phase LTP and long-term memory in normal and ageing hippocampus: role of secreted proteins tPA and BDNF. Age. Res. Rev. 3, 407–430 (2004).

    CAS  Article  Google Scholar 

  90. 90

    Savitz, J., Solms, M. & Ramesar, R. The molecular genetics of cognition: dopamine, COMT, and BDNF. Genes Brain Behav. 5, 311–328 (2006). This paper provides an excellent review of the research examining the relationship between genetic variability and cognitive functioning with an emphasis on dopamine receptor genes, catechol-O-methyltransferase ( COMT ) and brain-derived neurotrophic factor ( BDNF).

    CAS  PubMed  Article  Google Scholar 

  91. 91

    Egan, M. F. et al. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 112, 257–269 (2003).

    CAS  Article  Google Scholar 

  92. 92

    Hariri, A. R. et al. Brain-derived neurotrophic factor val66met polymorphism affects human memory-related hippocampal activity and predicts memory performance. J. Neurosci. 23, 6690–6694 (2003).

    CAS  Article  Google Scholar 

  93. 93

    Pezawas, L. et al. The brain-derived neurotrophic factor val66met polymorphism and variation in human cortical morphology. J. Neurosci. 24, 10099–10102 (2004).

    CAS  PubMed  Article  Google Scholar 

  94. 94

    McAllister, T. W. et al. Cognitive effects of cytotoxic cancer chemotherapy: predisposing risk factors and potential treatments. Curr. Psych. Rep. 6, 364–371 (2004).

    Article  Google Scholar 

  95. 95

    Weinberger, D. R. et al. Prefrontal neurons and the genetics of schizophrenia. Biol. Psychiatry 50, 825–844 (2001).

    CAS  Article  Google Scholar 

  96. 96

    Malhotra, A. K. et al. A functional polymorphism in the COMT gene and performance on a test of prefrontal cognition. Am. J. Psych. 159, 652–654 (2001).

    Article  Google Scholar 

  97. 97

    Zec, R. F. & Trivedi, M. A. The effects of estrogen replacement therapy on neuropsychological functioning in postmenopausal women with and without dementia: a critical and theoretical review. Neuropsychol. Rev. 12, 65–109 (2002).

    PubMed  Article  Google Scholar 

  98. 98

    Bender, D. M., Paraska, K. K., Sereika, S. M., Ryan, C. M. & Berga, S. L. Cognitive function and reproductive hormones in adjuvant therapy for breast cancer: a critical review. J. Pain Sympt. Manage. 21, 407–424 (2001).

    CAS  Article  Google Scholar 

  99. 99

    Jenkins, V. A., Bloomfield, D. J., Shilling, V. M. & Edginton, T. L. Does neoadjuvant hormone therapy for early prostate cancer affect cognition? Results from a pilot study. Br. J. Urol. 96, 48–53 (2005).

    CAS  Article  Google Scholar 

  100. 100

    Unfer, T. C. et al. Influence of hormone replacement therapy on blood antioxidant enzymes in menopausal women. Clin. Chim. Acta 369, 73–77 (2006).

    CAS  PubMed  Article  Google Scholar 

  101. 101

    Chisu, V., Lepore, M. G., Zedda, M. & Farina, V. Testosterone induces neuroprotection from oxidative stress. Effects on catalase activity and 3-Nitro-L-styrosine incorporation into α-tubulin in a mouse neuroblastoma cell line. Arch. Ital. Biol. 144, 63–73 (2006).

    CAS  PubMed  Google Scholar 

  102. 102

    Lee, D.-C., Im, J.-A., Kim, J.-H., Lee, H.-R. & Shim, J.-Y. Effect of long-term hormone therapy on telomere length in postmenopausal women. Yonsei Med. J. 46, 471–479 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  103. 103

    Theodoulou M. & Seidman, A. D. Cardiac effects of adjuvant therapy for early breast cancer. Semin. Oncol. 30, 730–739 (2003).

    CAS  PubMed  Article  Google Scholar 

  104. 104

    Miller, D. B. & O' Callaghan, J. P. Aging, stress and the hippocampus. Age. Res. Rev. 4, 123–140 (2005).

    CAS  Article  Google Scholar 

  105. 105

    Hukovic, N. & Brown E. S. Effects of prescription corticosteroids on mood and cognition. Adv. Psychosom. Med. 24, 161–167 (2003).

    PubMed  Article  Google Scholar 

  106. 106

    Lee, G. D. et al. Transient improvement in cognitive function and synaptic plasticity in rats following cancer chemotherapy. Clin. Cancer Res. 12, 198–205 (2006).

    CAS  PubMed  Article  Google Scholar 

  107. 107

    Winocur, G., Vardy, J, Bims, M. A., Kerr, L. & Tannock, I. The effects of the anti-cancer drugs, methotrexate and 5-fluorouracil, on cognitive function in mice. Pharmacol. Biochem. Behav. 85, 66–75 (2006). These investigators developed an animal model of chemotherapy-induced cognitive deficits and showed deficits in memory and learning tasks in mice treated with chemotherapy that were similar to deficits seen in breast cancer survivors.

    CAS  PubMed  Article  Google Scholar 

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Acknowledgements

The authors are supported by grants from the Office of Cancer Survivorship of the US National Cancer Institute and a National Institutes of Health Roadmap U54 Grant.

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Glossary

Magnetic resonance imaging

A noninvasive technique that produces high-resolution, computerized images of internal body tissues. Structural MRI enables abnormalities of brain structure to be evaluated and volumetric measurements of specific structures to be made. Functional MRI enables activation patterns in various brain areas in response to the performance of cognitive or motor tasks to be examined.

P-300

The P-300 is a neural-evoked potential component of the EEG. The P-300 is an event-related potential that is triggered approximately 300 milliseconds after the presentation of an unexpected or novel stimulus.

Encephalopathy

Encephalopathy refers to alterations in brain structure and/or function that can have several causes, including infection, exposure to toxic chemicals (for example, chemotherapy), poor nutrition or lack of oxygen or blood flow to the brain. The primary symptoms of encephalopathy are alterations in mental status.

Leukoencephalopathy

Alterations of the white matter of the brain owing to infection or exposure to toxic chemicals.

Ototoxicity

Toxicity associated with organs or nerves involved with hearing or balance.

Cerebellar symptoms

The cerebellum is an area of the brain that is important for the integration of sensory input and motor output. Disorders of the cerebellum include symptoms associated with equilibrium, posture, motor learning and fine motor control.

Positron emission tomography

A nuclear medicine imaging technique that produces a three-dimensional image of functional or metabolic processes in the body by scanning for a radioactive isotope (for example, a radiolabelled chemotherapy agent) that has been injected into the bloodstream.

Ataxia telangiectasia

A disorder caused by a mutation of the ataxia telangiectasia mutated (ATM) gene, which is important for DNA repair. Ataxia telangiectasia causes progressive immunological and neurological problems, including cognitive symptoms, and people with ataxia telangiectasia have a significantly increased risk of cancer.

Xeroderma pigmentosum

A genetic DNA-repair disorder in which the body is unable to repair DNA damage or mutations caused by ultraviolet light.

Glia

A group of non-neuronal cells in the brain that provide support and nutrition, form myelin and influence signal transmission in the nervous system.

Sickness behaviour

Physiological response to infection that includes symptoms such as decreased activity level, fatigue, decreased motivation and cognitive problems.

Vagus nerve

The vagus nerve is the only cranial nerve that extends from the brainstem to all the organs in the abdomen.

Excitotoxicity

The process by which neurons are damaged or killed through the over-activation of receptors for the excitatory neurotransmitter glutamate.

Long-term potentiation

Long-lasting increase in the functioning of a synapse, which is thought to be related to neural plasticity and the cellular basis for learning and memory.

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Ahles, T., Saykin, A. Candidate mechanisms for chemotherapy-induced cognitive changes. Nat Rev Cancer 7, 192–201 (2007). https://doi.org/10.1038/nrc2073

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