Clinical characteristics, pathophysiology, and management of noncentral nervous system cancer-related cognitive impairment in adults

Jeffrey S Wefel, Shelli R Kesler, Kyle R Noll, Sanne B Schagen, Jeffrey S Wefel, Shelli R Kesler, Kyle R Noll, Sanne B Schagen

Abstract

Answer questions and earn CME/CNE Over the past few decades, a body of research has emerged confirming what many adult patients with noncentral nervous system cancer have long reported-that cancer and its treatment are frequently associated with cancer-related cognitive impairment (CRCI). The severity of CRCI varies, and symptoms can emerge early or late in the disease course. Nonetheless, CRCI is typically mild to moderate in nature and primarily involves the domains of memory, attention, executive functioning, and processing speed. Animal models and novel neuroimaging techniques have begun to unravel the pathophysiologic mechanisms underlying CRCI, including the role of inflammatory cascades, direct neurotoxic effects, damage to progenitor cells, white matter abnormalities, and reduced functional connectivity, among others. Given the paucity of research on CRCI with other cancer populations, this review synthesizes the current literature with a deliberate focus on CRCI within the context of breast cancer. A hypothetical case-study approach is used to illustrate how CRCI often presents clinically and how current science can inform practice. While the literature regarding intervention for CRCI is nascent, behavioral and pharmacologic approaches are discussed.

Keywords: breast neoplasms; chemotherapy; complications and late effects of therapy; psychological/behavioral oncology.

Conflict of interest statement

The remaining authors report no conflicts of interest.

© 2014 American Cancer Society.

References

    1. 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;3:223–232.
    1. Nelson WL, Suls J. New approaches to understand cognitive changes associated with chemotherapy for non-central nervous system tumors. J Pain Symptom Manage. 2013;46:707–721.
    1. Weiss HD, Walker MD, Wiernik PH. Neurotoxicity of commonly used antineoplastic agents (first of two parts) N Engl J Med. 1974;291:75–81.
    1. Ahles TA, Saykin AJ. Candidate mechanisms for chemotherapy-induced cognitive changes. Nat Rev Cancer. 2007;7:192–201.
    1. Ouimet LA, Stewart A, Collins B, Schindler D, Bielajew C. Measuring neuropsychological change following breast cancer treatment: an analysis of statistical models. J Clin Exp Neuropsychol. 2009;31:73–89.
    1. Ahles TA, Saykin AJ. Breast cancer chemotherapy-related cognitive dysfunction. Clin Breast Cancer. 2002;3(suppl 3):S84–S90.
    1. Bender CM, Sereika SM, Berga SL, et al. Cognitive impairment associated with adjuvant therapy in breast cancer. Psychooncology. 2006;15:422–430.
    1. Castellon SA, Ganz PA, Bower JE, Petersen L, Abraham L, Greendale GA. Neurocognitive performance in breast cancer survivors exposed to adjuvant chemotherapy and tamoxifen. J Clin Exp Neuropsychol. 2004;26:955–969.
    1. Donovan KA, Small BJ, Andrykowski MA, Schmitt FA, Munster P, Jacobsen PB. Cognitive functioning after adjuvant chemotherapy and/or radiotherapy for early stage breast carcinoma. Cancer. 2005;104:2499–2507.
    1. Gottschalk LA, Holcombe RF, Jackson D, Bechtel RJ. The effects of anticancer chemotherapeutic drugs on cognitive function and other neuropsychiatric dimensions in breast cancer patients. Methods Find Exp Clin Pharmacol. 2003;25:117–122.
    1. Hermelink K, Untch M, Lux MP, et al. Cognitive function during neoadjuvant chemotherapy for breast cancer: results of a prospective, multicenter, longitudinal study. Cancer. 2007;109:1905–1913.
    1. Mandelblatt JS, Hurria A, McDonald BC, et al. Cognitive effects of cancer and its treatments at the intersection of aging: what do we know; what do we need to know? Semin Oncol. 2013;40:709–725.
    1. Jenkins V, Shilling V, Deutsch G, 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. 2006;94:828–834.
    1. Stewart A, Collins B, Mackenzie J, Tomiak E, Verma S, Bielajew C. The cognitive effects of adjuvant chemotherapy in early stage breast cancer: a prospective study. Psychooncology. 2008;17:122–130.
    1. Debess J, Riis JO, Pedersen L, Ewertz M. Cognitive function and quality of life after surgery for early breast cancer in North Jutland, Denmark. Acta Oncol. 2009;48:532–540.
    1. Scherling C, Collins B, Mackenzie J, Bielajew C, Smith A. Pre-chemotherapy differences in visuospatial working memory in breast cancer patients compared to controls: an FMRI study [serial online] Front Hum Neurosci. 2011;5:122.
    1. Chen ML, Miaskowski C, Liu LN, Chen SC. Changes in perceived attentional function in women following breast cancer surgery. Breast Cancer Res Treat. 2012;131:599–606.
    1. Wefel JS, Lenzi R, Theriault R, Buzdar AU, Cruickshank S, Meyers CA. ‘Chemobrain’ in breast carcinoma?: a prologue. Cancer. 2004;101:466–475.
    1. Ernst T, Chang L, Cooray D, et al. The effects of tamoxifen and estrogen on brain metabolism in elderly women. J Natl Cancer Inst. 2002;94:592–597.
    1. Schilder CM, Seynaeve C, Beex LV, et al. Effects of tamoxifen and exemestane on cognitive functioning of postmenopausal patients with breast cancer: results from the neuropsychological side study of the tamoxifen and exemestane adjuvant multinational trial. J Clin Oncol. 2010;28:1294–1300.
    1. Shilling V, Jenkins V, Fallowfield L, Howell T. The effects of hormone therapy on cognition in breast cancer. J Steroid Biochem Mol Biol. 2003;86:405–412.
    1. Janelsins MC, Kesler SR, Ahles TA, Morrow GR. Prevalence, mechanisms, and management of cancer-related cognitive impairment. Int Rev Psychiatry. 2014;26:102–113.
    1. Ahles TA, Saykin AJ, McDonald BC, et al. Cognitive function in breast cancer patients prior to adjuvant treatment. Breast Cancer Res Treat. 2008;110:143–152.
    1. 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;19:1647–1656.
    1. Wefel JS, Saleeba AK, Buzdar AU, Meyers CA. Acute and late onset cognitive dysfunction associated with chemotherapy in women with breast cancer. Cancer. 2010;116:3348–3356.
    1. Perry A, Schmidt RE. Cancer therapy-associated CNS neuropathology: an update and review of the literature. Acta Neuropathol. 2006;111:197–212.
    1. Videnovic A, Semenov I, Chua-Adajar R, et al. Capecitabine-induced multifocal leukoencephalopathy: a report of five cases. Neurology. 2005;65:1792–1794. discussion 1685.
    1. Ahles TA, Saykin AJ, Furstenberg CT, et al. Neuropsychologic impact of standard-dose systemic chemotherapy in long-term survivors of breast cancer and lymphoma. J Clin Oncol. 2002;20:485–493.
    1. Wefel JS, Schagen SB. Chemotherapy-related cognitive dysfunction. Curr Neurol Neurosci Rep. 2012;12:267–275.
    1. Janelsins MC, Kohli S, Mohile SG, Usuki K, Ahles TA, Morrow GR. An update on cancer- and chemotherapy-related cognitive dysfunction: current status. Semin Oncol. 2011;38:431–438.
    1. DeSantis CE, Lin CC, Mariotto AB, et al. Cancer treatment and survivorship statistics, 2014. CA Cancer J Clin. 2014;64:252–271.
    1. Pedersen AD, Rossen P, Mehlsen MY, Pedersen CG, Zachariae R, von der Maase H. Long-term cognitive function following chemotherapy in patients with testicular cancer. J Int Neuropsychol Soc. 2009;15:296–301.
    1. Wefel JS, Vidrine DJ, Marani SK, et al. A prospective study of cognitive function in men with non-seminomatous germ cell tumors. Psychooncology. 2014;23:626–633.
    1. Jones D, Vichaya EG, Wang XS, Sailors MH, Cleeland CS, Wefel JS. Acute cognitive impairment in patients with multiple myeloma undergoing autologous hematopoietic stem cell transplant. Cancer. 2013;119:4188–4195.
    1. Vardy JL, Booth C, Pond GR, et al. Cytokine levels in patients (pts) with colorectal cancer and breast cancer and their relationship to fatigue and cognitive function [abstract] J Clin Oncol. 2007;25(18S):Abstract 9070.
    1. Correa DD, Hess LM. Cognitive function and quality of life in ovarian cancer. Gynecol Oncol. 2012;124:404–409.
    1. Chao HH, Uchio E, Zhang S, et al. Effects of androgen deprivation on brain function in prostate cancer patients—a prospective observational cohort analysis [serial online] BMC Cancer. 2012;12:371.
    1. Lange M, Giffard B, Noal S, et al. Baseline cognitive functions among elderly patients with localised breast cancer. Eur J Cancer. 2014;50:2181–2189.
    1. Kinsinger SW, Lattie E, Mohr DC. Relationship between depression, fatigue, subjective cognitive impairment, and objective neuropsychological functioning in patients with multiple sclerosis. Neuropsychology. 2010;24:573–580.
    1. Slavin MJ, Brodaty H, Kochan NA, et al. Prevalence and predictors of “subjective cognitive complaints” in the Sydney Memory and Ageing Study. Am J Geriatr Psychiatry. 2010;18:701–710.
    1. Cicerone KD, Kalmar K. Persistent post-concussion syndrome: the structure of subjective complaints after mild traumatic brain injury. J Head Trauma Rehabil. 1995;10:1–17.
    1. Ganz PA, Kwan L, Castellon SA, et al. Cognitive complaints after breast cancer treatments: examining the relationship with neuropsychological test performance. J Natl Cancer Inst. 2013;105:791–801.
    1. Shilling V, Jenkins V. Self-reported cognitive problems in women receiving adjuvant therapy for breast cancer. Eur J Oncol Nurs. 2007;11:6–15.
    1. Pullens MJ, De Vries J, Roukema JA. Subjective cognitive dysfunction in breast cancer patients: a systematic review. Psychooncology. 2010;19:1127–1138.
    1. Pullens MJ, De Vries J, Van Warmerdam LJ, Van De Wal MA, Roukema JA. Chemotherapy and cognitive complaints in women with breast cancer. Psychooncology. 2013;22:1783–1789.
    1. Cimprich B, Ronis DL, Trask C. Pre-treatment factors related to cognitive functioning in women newly diagnosed with breast cancer. Psychooncology. 2005;14:70–78.
    1. Mandelblatt JS, Stern RA, Luta G, et al. Cognitive impairment in older patients with breast cancer before systemic therapy: is there an interaction between cancer and comorbidity? J Clin Oncol. 2014;32:1909–1918.
    1. Evered L, Scott DA, Silbert B, Maruff P. Postoperative cognitive dysfunction is independent of type of surgery and anesthetic. Anesth Analg. 2011;112:1179–1185.
    1. Seigers R, Fardell JE. Neurobiological basis of chemotherapy-induced cognitive impairment: a review of rodent research. Neurosci Biobehav Rev. 2011;35:729–741.
    1. Yang M, Kim J, Kim J-S, et al. Hippocampal dysfunctions in tumor-bearing mice. Brain Behav Immun. 2014;36:147–155.
    1. Schagen SB, Muller MJ, Boogerd W, et al. Late effects of adjuvant chemotherapy on cognitive function: a follow-up study in breast cancer patients. Ann Oncol. 2002;13:1387–1397.
    1. Wefel JS, Lenzi R, Theriault RL, Davis RN, Meyers CA. The cognitive sequelae of standard-dose adjuvant chemotherapy in women with breast carcinoma: results of a prospective, randomized, longitudinal trial. Cancer. 2004;100:2292–2299.
    1. Mar Fan HG, Houede-Tchen N, Yi Q-L, et al. Fatigue, menopausal symptoms, and cognitive function in women following adjuvant chemotherapy for breast cancer with or without subsequent tamoxifen: one and two year follow-up of a prospective controlled study. Breast Cancer Res Treat. 2004;88:S138–S138.
    1. Shilling V, Jenkins V, Morris R, Deutsch G, Bloomfield D. The effects of adjuvant chemotherapy on cognition in women with breast cancer—preliminary results of an observational longitudinal study. Breast. 2005;14:142–150.
    1. Hurria A, Rosen C, Hudis C, et al. Cognitive function of older patients receiving adjuvant chemotherapy for breast cancer: a pilot prospective longitudinal study. J Am Geriatr Soc. 2006;54:925–931.
    1. Schagen SB, Muller MJ, Boogerd W, Mellenbergh GJ, van Dam FS. Change in cognitive function after chemotherapy: a prospective longitudinal study in breast cancer patients. J Natl Cancer Inst. 2006;98:1742–1745.
    1. Minisini AM, De Faccio S, Ermacora P, et al. Cognitive functions and elderly anti-cancer treatment: a cancer patients receiving prospective study. Crit Rev Oncol Hematol. 2008;67:71–79.
    1. Jansen CE, Dodd MJ, Miaskowski CA, Dowling GA, Kramer J. Preliminary results of a longitudinal study of changes in cognitive function in breast cancer patients undergoing chemotherapy with doxorubicin and cyclophosphamide. Psychooncology. 2008;17:1189–1195.
    1. Collins B, Mackenzie J, Tasca GA, Scherling C, Smith A. Persistent cognitive changes in breast cancer patients 1 year following completion of chemotherapy. J Int Neuropsychol Soc. 2014;20:370–379.
    1. Quesnel C, Savard J, Ivers H. Cognitive impairments associated with breast cancer treatments: results from a longitudinal study. Breast Cancer Res Treat. 2009;116:113–123.
    1. Vearncombe KJ, Rolfe M, Wright M, Pachana NA, Andrew B, Beadle G. Predictors of cognitive decline after chemotherapy in breast cancer patients. J Int Neuropsychol Soc. 2009;15:951–962.
    1. Ahles TA, Saykin AJ, McDonald BC, et al. Longitudinal assessment of cognitive changes associated with adjuvant treatment for breast cancer: impact of age and cognitive reserve. J Clin Oncol. 2010;28:4434–4440.
    1. Kvale EA, Clay OJ, Ross-Meadows LA, et al. Cognitive speed of processing and functional declines in older cancer survivors: an analysis of data from the ACTIVE trial. Eur J Cancer Care. 2010;19:110–117.
    1. Reid-Arndt SA, Hsieh C, Perry MC. Neuropsychological functioning and quality of life during the first year after completing chemotherapy for breast cancer. Psychooncology. 2010;19:535–544.
    1. Tager FA, McKinley PS, Schnabel FR, et al. The cognitive effects of chemotherapy in post-menopausal breast cancer patients: a controlled longitudinal study. Breast Cancer Res Treat. 2010;123:25–34.
    1. Deprez S, Amant F, Yigit R, 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;32:480–493.
    1. Biglia N, Bounous VE, Malabaila A, et al. Objective and self-reported cognitive dysfunction in breast cancer women treated with chemotherapy: a prospective study. Eur J Cancer Care. 2012;21:485–492.
    1. Wieneke MH, Dienst ER. Neuropsychological assessment of cognitive-functioning following chemotherapy for breast-cancer. Psychooncology. 1995;4:61–66.
    1. van Dam FS, Schagen SB, Muller MJ, et al. Impairment of cognitive function in women receiving adjuvant treatment for high-risk breast cancer: high-dose versus standard-dose chemotherapy. J Natl Cancer Inst. 1998;90:210–218.
    1. Collins B, MacKenzie J, Tasca GA, Scherling C, Smith A. Cognitive effects of chemotherapy in breast cancer patients: a dose-response study. Psychooncology. 2013;22:1517–1527.
    1. Palmer JL, Trotter T, Joy AA, Carlson LE. Cognitive effects of tamoxifen in pre-menopausal women with breast cancer compared to healthy controls. J Cancer Surviv. 2008;2:275–282.
    1. Batalo M, Nagaiah G, Abraham J. Cognitive dysfunction in postmenopausal breast cancer patients on aromatase inhibitors. Expert Rev Anticancer Ther. 2011;11:1277–1282.
    1. Jenkins V, Shilling V, Fallowfield L, Howell A, Hutton S. Does hormone therapy for the treatment of breast cancer have a detrimental effect on memory and cognition? A pilot study. Psychooncology. 2004;13:61–66.
    1. Jenkins VA, Ambroisine LM, Atkins L, Cuzick J, Howell A, Fallowfield LJ. Effects of anastrozole on cognitive performance in postmenopausal women: a randomised, double-blind chemoprevention trial (IBIS II) Lancet Oncol. 2008;9:953–961.
    1. Phillips KA, Ribi K, Sun ZX, et al. Cognitive function in postmenopausal women receiving adjuvant letrozole or tamoxifen for breast cancer in the BIG 1–98 randomized trial. Breast. 2010;19:388–395.
    1. Burstein HJ, Temin S, Anderson H, et al. Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: American Society of Clinical Oncology clinical practice guideline focused update. J Clin Oncol. 2014;32:2255–2269.
    1. Kierkegaard M, Einarsson U, Gottberg K, von Koch L, Holmqvist LW. The relationship between walking, manual dexterity, cognition and activity/participation in persons with multiple sclerosis. Mult Scler. 2012;18:639–646.
    1. Reid-Arndt SA, Yee A, Perry MC, Hsieh C. Cognitive and psychological factors associated with early posttreatment functional outcomes in breast cancer survivors. J Psychosoc Oncol. 2009;27:415–434.
    1. Myers JS. Chemotherapy-related cognitive impairment: the breast cancer experience. Oncol Nurs Forum. 2012;39:E31–E40.
    1. Short PF, Vasey JJ, Tunceli K. Employment pathways in a large cohort of adult cancer survivors. Cancer. 2005;103:1292–1301.
    1. 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;30:1080–1086.
    1. Salthouse TA. Neuroanatomical substrates of age-related cognitive decline [serial online] Psychol Bull. 2011;137:753.
    1. Nicoll J, Savva G, Stewart J, Matthews F, Brayne C, Ince P. Association between APOE genotype, neuropathology and dementia in the older population of England and Wales. Neuropathol Appl Neurobiol. 2011;37:285–294.
    1. Wefel JS, Vardy J, Ahles T, Schagen SB. International Cognition and Cancer Task Force recommendations to harmonise studies of cognitive function in patients with cancer. Lancet Oncol. 2011;12:703–708.
    1. Kaiser J, Dietrich J. Challenges in research on the neural basis of “chemobrain”. Translational Neurosci. 2014;5:222–225.
    1. Monje M, Dietrich J. Cognitive side effects of cancer therapy demonstrate a functional role for adult neurogenesis. Behav Brain Res. 2012;227:376–379.
    1. Seigers R, Schagen SB, Van Tellingen O, Dietrich J. Chemotherapy-related cognitive dysfunction: current animal studies and future directions. Brain Imaging Behav. 2013;7:453–459.
    1. Pereira Dias G, Hollywood R, Bevilaqua MC, et al. Consequences of cancer treatments on adult hippocampal neurogenesis: implications for cognitive function and depressive symptoms. Neuro Oncol. 2014;16:476–492.
    1. Han R, Yang YM, Dietrich J, Luebke A, Mayer-Proschel M, Noble M. Systemic 5-fluorouracil treatment causes a syndrome of delayed myelin destruction in the central nervous system [serial online] J Biol. 2008;7:12.
    1. 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 [serial online] J Biol. 2006;5:22.
    1. Briones T, Woods J, Wadowska M. Chronic neuroinflammation and cognitive impairment following transient global cerebral ischemia: role of fractalkine/ CX3CR1 signaling [serial online] J Neuroinflammation. 2014;11:13.
    1. Kaya E, Keskin L, Aydogdu I, Kuku I, Bayraktar N, Erkut M. Oxidant/antioxidant parameters and their relationship with chemotherapy in Hodgkin’s lymphoma. J Int Med Res. 2005;33:687–692.
    1. Smith J, Ladi E, Mayer-Proschel M, Noble M. Redox state is a central modulator of the balance between self-renewal and differentiation in a dividing glial precursor cell. Proc Natl Acad Sci U S A. 2000;97:10032–10037.
    1. Seigers R, Timmermans J, van der Horn HJ, et al. Methotrexate reduces hippocampal blood vessel density and activates microglia in rats but does not elevate central cytokine release. Behav Brain Res. 2010;207:265–272.
    1. Helal GK, Aleisa AM, Helal OK, et al. Metallothionein induction reduces caspase-3 activity and TNFalpha levels with preservation of cognitive function and intact hippocampal neurons in carmustine-treated rats. Oxid Med Cell Longev. 2009;2:26–35.
    1. Madhyastha S, Somayaji S, Rao M, Nalini K, Bairy KL. Hippocampal brain amines in methotrexate-induced learning and memory deficit. Can J Physiol Pharmacol. 2002;80:1076–1084.
    1. Landry M, Di Paolo T. Effect of chronic estradiol, tamoxifen or raloxifene treatment on serotonin 5-HT1A receptor. Brain Res Mol Brain Res. 2003;112:82–89.
    1. Bethea CL, Mirkes SJ, Su A, Michelson D. Effects of oral estrogen, raloxifene and arzoxifene on gene expression in serotonin neurons of macaques. Psychoneuroendocrinology. 2002;27:431–445.
    1. Cyr M, Landry M, Di Paolo T. Modulation by estrogen-receptor directed drugs of 5-hydroxytryptamine-2A receptors in rat brain. Neuropsychopharmacology. 2000;23:69–78.
    1. Grassi S, Tozzi A, Costa C, et al. Neural 17β-estradiol facilitates long-term potentiation in the hippocampal CA1 region. Neuroscience. 2011;192:67–73.
    1. Aydin M, Yilmaz B, Alcin E, Nedzvetsky VS, Sahin Z, Tuzcu M. Effects of letrozole on hippocampal and cortical catecholaminergic neurotransmitter levels, neural cell adhesion molecule expression and spatial learning and memory in female rats. Neuroscience. 2008;151:186–194.
    1. Mook D, Felger J, Graves F, Wallen K, Wilson ME. Tamoxifen fails to affect central serotonergic tone but increases indices of anxiety in female rhesus macaques. Psychoneuroendocrinology. 2005;30:273–283.
    1. Chen D, Wu CF, Shi B, Xu YM. Tamoxifen and toremifene cause impairment of learning and memory function in mice. Pharmacol Biochem Behav. 2002;71:269–276.
    1. Kokiko ON, Murashov AK, Hoane MR. Administration of raloxifene reduces sensorimotor and working memory deficits following traumatic brain injury. Behav Brain Res. 2006;170:233–240.
    1. Moradpour F, Naghdi N, Fathollahi Y. Anastrozole improved testosterone-induced impairment acquisition of spatial learning and memory in the hippocampal CA1 region in adult male rats. Behav Brain Res. 2006;175:223–232.
    1. Abraham J, Haut M, Moran M, Filburn S, Lemiuex S, Kuwabara H. Adjuvant chemotherapy for breast cancer: effects on cerebral white matter seen in diffusion tensor imaging. Clin Breast Cancer. 2008;8:88–91.
    1. Bergouignan L, Lefranc JP, Chupin M, Morel N, Spano JP, Fossati P. Breast cancer affects both the hippocampus volume and the episodic autobiographical memory retrieval [serial online] PLoS One. 2011;6:e25349.
    1. Conroy SK, McDonald BC, Smith DJ, et al. Alterations in brain structure and function in breast cancer survivors: effect of post-chemotherapy interval and relation to oxidative DNA damage. Breast Cancer Res Treat. 2013;137:493–502.
    1. de Ruiter MB, Reneman L, Boogerd W, 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;33:2971–2983.
    1. Deprez S, Amant F, Smeets A, et al. Longitudinal assessment of chemotherapy-induced structural changes in cerebral white matter and its correlation with impaired cognitive functioning. J Clin Oncol. 2012;30:274–281.
    1. Eberling JL, Wu C, Tong-Turnbeaugh R, Jagust WJ. Estrogen- and tamoxifen-associated effects on brain structure and function. Neuroimage. 2004;21:364–371.
    1. Hosseini SM, Koovakkattu D, Kesler SR. Altered small-world properties of gray matter networks in breast cancer [serial online] BMC Neurol. 2012;12:28.
    1. Inagaki M, Yoshikawa E, Matsuoka Y, et al. Smaller regional volumes of brain gray and white matter demonstrated in breast cancer survivors exposed to adjuvant chemotherapy. Cancer. 2007;109:146–156.
    1. Kesler S, Janelsins M, Koovakkattu D, et al. 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. 2013;30(suppl):S109–S116.
    1. Koppelmans V, de Groot M, de Ruiter MB, et al. Global and focal white matter integrity in breast cancer survivors 20 years after adjuvant chemotherapy. Hum Brain Mapp. 2014;35:889–899.
    1. Koppelmans V, de Ruiter MB, van der Lijn F, et al. Global and focal brain volume in long-term breast cancer survivors exposed to adjuvant chemotherapy. Breast Cancer Res Treat. 2012;132:1099–1106.
    1. McDonald BC, Conroy SK, Ahles TA, West JD, Saykin AJ. Gray matter reduction associated with systemic chemotherapy for breast cancer: a prospective MRI study. Breast Cancer Res Treat. 2010;123:819–828.
    1. McDonald BC, Conroy SK, Smith DJ, West JD, Saykin AJ. Frontal gray matter reduction after breast cancer chemotherapy and association with executive symptoms: a replication and extension study. Brain Behav Immun. 2013;30(suppl):S117–S125.
    1. Sporns O. The human connectome: a complex network. Ann NY Acad Sci. 2011;1224:109–125.
    1. Kesler SR. Default mode network as a potential biomarker of chemotherapy-related brain injury. Neurobiol Aging. 2014;35(suppl 2):S11–S19.
    1. Bruno J, Hosseini SM, Kesler S. Altered resting state functional brain network topology in chemotherapy-treated breast cancer survivors. Neurobiol Dis. 2012;48:329–338.
    1. Cimprich B, Reuter-Lorenz P, Nelson J, et al. Prechemotherapy alterations in brain function in women with breast cancer. J Clin Exp Neuropsychol. 2010;32:324–331.
    1. Conroy SK, McDonald BC, Ahles TA, West JD, Saykin AJ. Chemotherapy-induced amenorrhea: a prospective study of brain activation changes and neurocognitive correlates. Brain Imaging Behav. 2013;7:491–500.
    1. de Ruiter MB, Reneman L, Boogerd W, et al. Cerebral hyporesponsiveness and cognitive impairment 10 years after chemotherapy for breast cancer. Hum Brain Mapp. 2011;32:1206–1219.
    1. Deprez S, Vandenbulcke M, Peeters R, et al. Longitudinal assessment of chemotherapy-induced alterations in brain activation during multitasking and its relation with cognitive complaints. J Clin Oncol. 2014;32:2031–2038.
    1. Dumas JA, Makarewicz J, Schaubhut GJ, et al. Chemotherapy altered brain functional connectivity in women with breast cancer: a pilot study. Brain Imaging Behav. 2013;7:524–532.
    1. Ferguson RJ, McDonald BC, Saykin AJ, Ahles TA. Brain structure and function differences in monozygotic twins: possible effects of breast cancer chemotherapy. J Clin Oncol. 2007;25:3866–3870.
    1. Hosseini SM, Kesler SR. Multivariate pattern analysis of fMRI in breast cancer survivors and healthy women. J Int Neuropsychol Soc. 2013;19:1–11.
    1. Kesler SR, Kent JS, O’Hara R. Prefrontal cortex and executive function impairments in primary breast cancer. Arch Neurol. 2011;68:1447–1453.
    1. Kesler SR, Wefel JS, Hosseini SM, Cheung M, Watson CL, Hoeft F. Default mode network connectivity distinguishes chemotherapy-treated breast cancer survivors from controls. Proc Natl Acad Sci. 2013;110:11600–11605.
    1. Lopez Zunini RA, Scherling C, Wallis N, et al. Differences in verbal memory retrieval in breast cancer chemotherapy patients compared to healthy controls: a prospective fMRI study. Brain Imaging Behav. 2012;7:460–477.
    1. McDonald BC, Conroy SK, Ahles TA, West JD, Saykin AJ. Alterations in brain activation during working memory processing associated with breast cancer and treatment: a prospective functional magnetic resonance imaging study. J Clin Oncol. 2012;30:2500–2508.
    1. Scherling C, Collins B, Mackenzie J, Bielajew C, Smith A. Prechemotherapy differences in response inhibition in breast cancer patients compared to controls: a functional magnetic resonance imaging study. J Clin Exp Neuropsychol. 2012;34:543–560.
    1. Silverman DH, Dy CJ, Castellon SA, 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;103:303–311.
    1. Pomykala KL, Ganz PA, Bower JE, et al. The association between pro-inflammatory cytokines, regional cerebral metabolism, and cognitive complaints following adjuvant chemotherapy for breast cancer. Brain Imaging Behav. 2013;7:511–523.
    1. Ponto LL, Menda Y, Magnotta VA, Yamada TH, Denburg NL, Schultz SK. Frontal hypometabolism in elderly breast cancer survivors determined by [18 F]fluorodeoxyglucose (FDG) positron emission tomography (PET): a pilot study [published online ahead of print September 1, 2014] Int J Geriatr Psychiatry. 2014
    1. Nudelman KN, Wang Y, McDonald BC, et al. Altered cerebral blood flow one month after systemic chemotherapy for breast cancer: a prospective study using pulsed arterial spin labeling MRI perfusion [serial online] PLoS One. 2014;9:e96713.
    1. Mathan S, Smart A, Ververs T, Feuerstein M. Towards an index of cognitive efficacy EEG-based estimation of cognitive load among individuals experiencing cancer-related cognitive decline. Conf Proc IEEE Eng Med Bio Soc. 2010;2010:6595–6598.
    1. Hunter AM, Kwan L, Ercoli LM, et al. Quantitative electroencephalography biomarkers of cognitive complaints after adjuvant therapy in breast cancer survivors: a pilot study. Psychooncology. 2014;23:713–715.
    1. Kreukels BP, Hamburger HL, de Ruiter MB, et al. ERP amplitude and latency in breast cancer survivors treated with adjuvant chemotherapy. Clin Neurophysiol. 2008;119:533–541.
    1. Kreukels BP, Schagen SB, Ridderinkhof KR, Boogerd W, Hamburger HL, van Dam FS. Electrophysiological correlates of information processing in breast-cancer patients treated with adjuvant chemotherapy. Breast Cancer Res Treat. 2005;94:53–61.
    1. Kesler SR, Watson C, Koovakkattu D, et al. Elevated prefrontal myoinositol and choline following breast cancer chemotherapy. Brain Imaging Behav. 2013;7:501–510.
    1. Brown MS, Stemmer SM, Simon JH, et al. White matter disease induced by high-dose chemotherapy: longitudinal study with MR imaging and proton spectroscopy. Am J Neuroradiol. 1998;19:217–221.
    1. Koppelmans V, Breteler MM, Boogerd W, Seynaeve C, Schagen SB. Late effects of adjuvant chemotherapy for adult onset non-CNS cancer; cognitive impairment, brain structure and risk of dementia. Crit Rev Oncol Hematol. 2013;88:87–101.
    1. Stouten-Kemperman MM, de Ruiter MB, Koppelmans V, Boogerd W, Reneman L, Schagen SB. Neurotoxicity in breast cancer survivors ≥10 years post-treatment is dependent on treatment type [published online ahead of print May 25, 2014] Brain Imaging Behav. 2014
    1. Hurria A, Patel SK, Mortimer J, et al. The effect of aromatase inhibition on the cognitive function of older patients with breast cancer. Clin Breast Cancer. 2014;14:132–140.
    1. Ganz PA, Bower JE, Kwan L, et al. Does tumor necrosis factor-alpha (TNF-α) play a role in post-chemotherapy cerebral dysfunction? Brain Behav Immun. 2013;30:S99–S108.
    1. Zick SM, Zwickey H, Wood L, et al. Preliminary differences in peripheral immune markers and brain metabolites between fatigued and non-fatigued breast cancer survivors: a pilot study [published online ahead of print November 13, 2013] Brain Imaging Behav. 2013
    1. Askren MK, Jung M, Berman MG, et al. Neuromarkers of fatigue and cognitive complaints following chemotherapy for breast cancer: a prospective fMRI investigation. Breast Cancer Res Treat. 2014;147:445–455.
    1. Kim LS, Hwang HS, Jon DI, Ham BJ, Seok JH. Dysfunction of the neural network associated with sustained attention in cancer patients with clinically significant depressive symptoms. Neurosci Lett. 2008;447:1–6.
    1. Vardy J. Cognitive function in breast cancer survivors. Cancer Treat Res. 2009;151:387–419.
    1. Castellon S, Ganz PA. Neuropsychological studies in breast cancer: in search of chemobrain. Breast Cancer Res Treat. 2009;116:125–127.
    1. Zhang D, Shen D. Multi-modal multi-task learning for joint prediction of multiple regression and classification variables in Alzheimer’s disease. Neuroimage. 2012;59:895–907.
    1. Young J, Modat M, Cardoso MJ, et al. Accurate multimodal probabilistic prediction of conversion to Alzheimer’s disease in patients with mild cognitive impairment. Neuroimage Clin. 2013;2:735–745.
    1. Chincarini A, Bosco P, Calvini P, et al. Local MRI analysis approach in the diagnosis of early and prodromal Alzheimer’s disease. Neuroimage. 2011;58:469–480.
    1. Mahmoudi A, Takerkart S, Regragui F, Boussaoud D, Brovelli A. Multivoxel pattern analysis for FMRI data: a review [serial online] Comput Math Methods Med. 2012;2012:961257.
    1. O’Toole AJ, Jiang F, Abdi H, Penard N, Dunlop JP, Parent MA. Theoretical, statistical, and practical perspectives on pattern-based classification approaches to the analysis of functional neuroimaging data. J Cogn Neurosci. 2007;19:1735–1752.
    1. Orru G, Pettersson-Yeo W, Marquand AF, Sartori G, Mechelli A. Using Support Vector Machine to identify imaging biomarkers of neurological and psychiatric disease: a critical review. Neurosci Biobehav Rev. 2012;36:1140–1152.
    1. Cherrier MM, Anderson K, David D, et al. A randomized trial of cognitive rehabilitation in cancer survivors. Life Sci. 2013;93:617–622.
    1. Ercoli LM, Castellon SA, Hunter AM, et al. Assessment of the feasibility of a rehabilitation intervention program for breast cancer survivors with cognitive complaints. Brain Imaging Behav. 2013;7:543–553.
    1. Ferguson RJ, Ahles TA, Saykin AJ, et al. Cognitive-behavioral management of chemotherapy-related cognitive change. Psychooncology. 2007;16:772–777.
    1. Ferguson RJ, McDonald BC, Rocque MA, et al. Development of CBT for chemotherapy-related cognitive change: results of a waitlist control trial. Psychooncology. 2012;21:176–186.
    1. McDougall GJ, Becker H, Acee TW, Vaughan PW, Delville CL. Symptom management of affective and cognitive disturbance with a group of cancer survivors. Arch Psychiatr Nurs. 2011;25:24–35.
    1. Poppelreuter M, Weis J, Bartsch HH. Effects of specific neuropsychological training programs for breast cancer patients after adjuvant chemotherapy. J Psychosoc Oncol. 2009;27:274–296.
    1. Schuurs A, Green HJ. A feasibility study of group cognitive rehabilitation for cancer survivors: enhancing cognitive function and quality of life. Psychooncology. 2013;22:1043–1049.
    1. Kesler S, Hosseini SMH, Heckler C, et al. Cognitive training for improving executive function in chemotherapy-treated breast cancer survivors. Clin Breast Cancer. 2013;13:299–306.
    1. Von Ah D, Carpenter JS, Saykin A, et al. Advanced cognitive training for breast cancer survivors: a randomized controlled trial. Breast Cancer Res Treat. 2012;135:799–809.
    1. Galantino ML, Greene L, Daniels L, Dooley B, Muscatello L, O’Donnell L. Longitudinal impact of yoga on chemotherapy-related cognitive impairment and quality of life in women with early stage breast cancer: a case series. Explore. 2012;8:127–135.
    1. Janelsins M, Peppone L, Heckler C, et al. YOCAS yoga, fatigue, memory difficulty, and quality of life: results from a URCC CCOP randomized, controlled clinical trial among 358 cancer survivors [abstract] J Clin Oncol. 2012;30(suppl):Abstract 9142.
    1. Reid-Arndt SA, Matsuda S, Cox CR. Tai Chi effects on neuropsychological, emotional, and physical functioning following cancer treatment: a pilot study. Complement Ther Clin Pract. 2012;18:26–30.
    1. Oh B, Butow PN, Mullan BA, et al. Effect of medical Qigong on cognitive function, quality of life, and a biomarker of inflammation in cancer patients: a randomized controlled trial. Support Care Cancer. 2012;20:1235–1242.
    1. Alvarez J, Meyer FL, Granoff DL, Lundy A. The effect of EEG biofeedback on reducing postcancer cognitive impairment. Integr Cancer Ther. 2013;12:475–487.
    1. Cajigal S. Health insurers deny coverage for cognitive rehabilitation. Neurol Today. 2007;7:38–41.
    1. Steinkuehler C, Squire K, Barab S. Games, Learning and Society. New York, NY: Cambridge University Press; 2012.
    1. Wolinsky FD, Vander Weg MW, Howren MB, Jones MP, Dotson MM. A randomized controlled trial of cognitive training using a visual speed of processing intervention in middle aged and older adults [serial online] PLoS One. 2013;8:e61624.
    1. Valenzuela M, Sachdev P. Can cognitive exercise prevent the onset of dementia? Systematic review of randomized clinical trials with longitudinal follow-up. Am J Geriatr Psychiatry. 2009;17:179–187.
    1. Sanoff HK, Deal AM, Krishnamurthy J, et al. Effect of cytotoxic chemotherapy on markers of molecular age in patients with breast cancer [serial online] J Natl Cancer Inst. 2014;106:dju057.
    1. Ahles TA. Brain vulnerability to chemotherapy toxicities. Psychooncology. 2012;21:1141–1148.
    1. Anguera JA, Boccanfuso J, Rintoul JL, et al. Video game training enhances cognitive control in older adults. Nature. 2013;501:97–101.
    1. Jaeggi SM, Buschkuehl M, Shah P, Jonides J. The role of individual differences in cognitive training and transfer. Mem Cognit. 2013;42:464–480.
    1. Latham AJ, Patston LL, Tippett LJ. The virtual brain: 30 years of video-game play and cognitive abilities [serial online] Front Psychol. 2013;4:629.
    1. Haimov I, Shatil E. Cognitive training improves sleep quality and cognitive function among older adults with insomnia [serial online] PLoS One. 2013;8:e61390.
    1. Åkerlund E, Esbjornsson E, Sunnerhagen KS, Bjorkdahl A. Can computerized working memory training improve impaired working memory, cognition and psychological health? Brain Inj. 2013;27:1649–1657.
    1. Niman NB. The allure of games: toward an updated theory of the leisure class. Games Culture. 2013;8:25–42.
    1. Abuhamdeh S, Csikszentmihalyi M. The importance of challenge for the enjoyment of intrinsically motivated, goal-directed activities. Pers Soc Psychol Bull. 2012;38:317–330.
    1. Park DC, Bischof GN. The aging mind: neuroplasticity in response to cognitive training. Dialogues Clin Neurosci. 2013;15:109–119.
    1. Campbell KL, Neil SE, Winters-Stone KM. Review of exercise studies in breast cancer survivors: attention to principles of exercise training. Br J Sports Med. 2012;46:909–916.
    1. Voss MW, Vivar C, Kramer AF, van Praag H. Bridging animal and human models of exercise-induced brain plasticity. Trends Cogn Sci. 2013;17:525–544.
    1. Hayes SM, Hayes JP, Cadden M, Verfaellie M. A review of cardiorespiratory fitness-related neuroplasticity in the aging brain [serial online] Front Aging Neurosci. 2013;5:31.
    1. Hotting K, Roder B. Beneficial effects of physical exercise on neuroplasticity and cognition. Neurosci Biobehav Rev. 2013;37:2243–2257.
    1. Kramer AF, Erickson KI, Colcombe SJ. Exercise, cognition, and the aging brain. J Appl Physiol. 2006;101:1237–1242.
    1. Speisman RB, Kumar A, Rani A, Foster TC, Ormerod BK. Daily exercise improves memory, stimulates hippocampal neurogenesis and modulates immune and neuroimmune cytokines in aging rats. Brain Behav Immun. 2013;28:25–43.
    1. Blake H. Physical activity and exercise in the treatment of depression [serial online] Front Psychiatry. 2012;3:106.
    1. Marques-Aleixo I, Oliveira PJ, Moreira PI, Magalhaes J, Ascensao A. Physical exercise as a possible strategy for brain protection: evidence from mitochondrial-mediated mechanisms. Prog Neurobiol. 2012;99:149–162.
    1. Fardell JE, Vardy J, Shah JD, Johnston IN. Cognitive impairments caused by oxaliplatin and 5-fluorouracil chemotherapy are ameliorated by physical activity. Psychopharmacology. 2012;220:183–193.
    1. Ahlskog JE, Geda YE, Graff-Radford NR, Petersen RC. Physical exercise as a preventive or disease-modifying treatment of dementia and brain aging. Mayo Clin Proc. 2011;86:876–884.
    1. Snowden M, Steinman L, Mochan K, et al. Effect of exercise on cognitive performance in community-dwelling older adults: review of intervention trials and recommendations for public health practice and research. J Am Geriatr Soc. 2011;59:704–716.
    1. Hall PA, Fong G, Epp L, Elias LJ. Executive function moderates the intention-behavior link for physical activity and dietary behavior. Psychol Health. 2008;23:309–326.
    1. Hall PA, Zehr C, Paulitzki J, Rhodes R. Implementation intentions for physical activity behavior in older adult women: an examination of executive function as a moderator of treatment effects. Ann Behav Med. 2014;48:130–136.
    1. McAuley E, Mullen SP, Szabo AN, et al. Self-regulatory processes and exercise adherence in older adults: executive function and self-efficacy effects. Am J Prev Med. 2011;41:284–290.
    1. Best JR, Nagamatsu LS, Liu-Ambrose T. Improvements to executive function during exercise training predict maintenance of physical activity over the following year [serial online] Front Hum Neurosci. 2014;8:353.
    1. Hall PA, Elias LJ, Fong GT, Harrison AH, Borowsky R, Sarty GE. A social neuroscience perspective on physical activity. J Sport Exerc Psychol. 2008;30:432–449.
    1. Hofmann W, Schmeichel BJ, Baddeley AD. Executive functions and self-regulation. Trends Cogn Sci. 2012;16:174–180.
    1. Hong D, Scaletta Kent J, Kesler S. Cognitive profile of Turner syndrome. Dev Disabil Res Rev. 2009;15:270–278.
    1. Elliott R. Executive functions and their disorders. Br Med Bull. 2003;65:49–59.
    1. Krull KR, Annett RD, Pan Z, et al. Neurocognitive functioning and health-related behaviours in adult survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Eur J Cancer. 2011;47:1380–1388.
    1. Curlik DM, 2nd, Shors TJ. Training your brain: do mental and physical (MAP) training enhance cognition through the process of neurogenesis in the hippocampus? Neuropharmacology. 2013;64:506–514.
    1. Karr JE, Areshenkoff CN, Rast P, Garcia-Barrera MA. An empirical comparison of the therapeutic benefits of physical exercise and cognitive training on the executive functions of older adults: a meta-analysis of controlled trials [published online ahead of print June 16, 2014] Neuropsychology. 2014
    1. Kempermann G, Fabel K, Ehninger D, et al. Why and how physical activity promotes experience-induced brain plasticity [serial online] Front Neurosci. 2010;4:189.
    1. Fabel K, Wolf SA, Ehninger D, Babu H, Leal-Galicia P, Kempermann G. Additive effects of physical exercise and environmental enrichment on adult hippocampal neurogenesis in mice [serial online] Front Neurosci. 2009;3:50.
    1. Fabre C, Chamari K, Mucci P, Masse-Biron J, Prefaut C. Improvement of cognitive function by mental and/or individualized aerobic training in healthy elderly subjects. Int J Sports Med. 2002;23:415–421.
    1. Holzschneider K, Wolbers T, Roder B, Hotting K. Cardiovascular fitness modulates brain activation associated with spatial learning. Neuroimage. 2012;59:3003–3014.
    1. Gonzalez-Palau F, Franco M, Bamidis P, et al. The effects of a computer-based cognitive and physical training program in a healthy and mildly cognitive impaired aging sample. Aging Ment Health. 2014;18:838–846.
    1. Stern Y. Cognitive reserve. Neuropsychologia. 2009;47:2015–2028.
    1. Correa DD, Ahles TA. Neurocognitive changes in cancer survivors. Cancer J. 2008;14:396–400.
    1. Sulzer J, Haller S, Scharnowski F, et al. Real-time fMRI neurofeedback: progress and challenges. Neuroimage. 2013;76:386–399.
    1. Luber B, Lisanby SH. Enhancement of human cognitive performance using transcranial magnetic stimulation (TMS) Neuroimage. 2014;85:961–970.
    1. Demirtas-Tatlidede A, Vahabzadeh-Hagh AM, Pascual-Leone A. Can noninvasive brain stimulation enhance cognition in neuropsychiatric disorders? Neuropharmacology. 2013;64:566–578.
    1. Boggio PS, Valasek CA, Campanha C, et al. Non-invasive brain stimulation to assess and modulate neuroplasticity in Alzheimer’s disease. Neuropsychol Rehabil. 2011;21:703–716.
    1. Bloch Y, Harel EV, Aviram S, Govezensky J, Ratzoni G, Levkovitz Y. Positive effects of repetitive transcranial magnetic stimulation on attention in ADHD subjects: a randomized controlled pilot study. World J Biol Psychiatry. 2010;11:755–758.
    1. Fardell J, Vardy J, Johnston I, Winocur G. Chemotherapy and cognitive impairment: treatment options. Clin Pharmacol Ther. 2011;90:366–376.
    1. Gehring K, Roukema JA, Sitskoorn MM. Review of recent studies on interventions for cognitive deficits in patients with cancer. Expert Rev Anticancer Ther. 2012;12:255–269.
    1. Von Ah D, Storey S, Jansen CE, Allen DH. Coping strategies and interventions for cognitive changes in patients with cancer. Semin Oncol Nurs. 2013;29:288–299.
    1. Aluise CD, Miriyala S, Noel T, et al. 2-Mer-captoethane 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;50:1630–1638.
    1. Konat GW, Kraszpulski M, James I, Zhang HT, Abraham J. Cognitive dysfunction induced by chronic administration of common cancer chemotherapeutics in rats. Metab Brain Dis. 2008;23:325–333.
    1. Briones TL, Woods J, Wadowska M. Involvement of insulin-like growth factor-1 in chemotherapy-related cognitive impairment [published online ahead of print March 12, 2014] Behav Brain Res. 2014
    1. El Beltagy M, Mustafa S, Umka J, et al. Fluoxetine improves the memory deficits caused by the chemotherapy agent 5-fluo-rouracil. Behav Brain Res. 2010;208:112–117.
    1. Dubois M, Lapinte N, Villier V, et al. Chemotherapy-induced long-term alteration of executive functions and hippocampal cell proliferation: role of glucose as adjuvant. Neuropharmacology. 2014;79:234–248.
    1. Vijayanathan V, Gulinello M, Ali N, Cole PD. Persistent cognitive deficits, induced by intrathecal methotrexate, are associated with elevated CSF concentrations of excitotoxic glutamate analogs and can be reversed by an NMDA antagonist. Behav Brain Res. 2011;225:491–497.
    1. Cole PD, Vijayanathan V, Ali NF, et al. Memantine protects rats treated with intrathecal methotrexate from developing spatial memory deficits. Clin Cancer Res. 2013;19:4446–4454.

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