ReviewChemobrain: A systematic review of structural and functional neuroimaging studies
Introduction
Chemotherapy refers to the drugs used to treat cancer patients. These drugs are used to prevent cancer cells from multiplying, invading or spreading to other tissues. Most traditional chemotherapeutic agents appear to concentrate their effect on cell proliferation. Because cell proliferation is a characteristic of many normal cells, these agents also have toxic effects on normal cells (Skeel and Khleuf, 2007). Although the blood–brain barrier (BBB) provides some protection from systemic treatments, it is increasingly recognized that many agents gain access to this environment, via direct or indirect mechanisms, potentially contributing to central nervous system (CNS) toxicity. Some chemotherapeutic agents, for example antimetabolits (as metotrexate or fluorouracil), platinum-based agents or nitrosureas, have been associated with CNS neurological toxicity (Meyers and Perry, 2008). Moreover, several risk factors on developing neurotoxicity associated with chemotherapy have been identified, including exposure to high-dose regimens (Shah, 2005), additive effects of concurrent radiotherapy administration (Sheline et al., 1980, Sul and DeAngelis, 2006), intraarterial administration with BBB disruption or intrathecal administration (Delattre and Posner, 1995). Thus, the type, dose and administration route of chemotherapy are all variables of substantial importance in understanding the effect of chemotherapy on cognitive functions.
‘Chemobrain’ is the term used to describe the alterations in cognitive functioning reflecting the CNS toxic effects of systemic chemotherapy. Chemotherapy-related cognitive dysfunction has become a growing matter of interest in the last ten years (Meyers and Perry, 2008). This is due to the increasing population of cancer survivors in recent years as a result of the relevant advances in cancer therapy. Although acute cognitive changes during chemotherapy are common (Ahles and Saykin, 2002, Ferguson and Ahles, 2003), long-term post-treatment cognitive changes seem to persist in only a subgroup (17–34%) of cancer survivors (Ahles and Saykin, 2007).
Reported chemotherapy-induced cognitive effects are generally modest, remaining within normal limits but with a clear impact on everyday functioning (Tannock et al., 2004). Nevertheless, the affected domains have been remarkably consistent, with the greatest differences noted in processing speed, executive functions, working memory and certain aspects of episodic memory (Jansen et al., 2005).
Mechanisms underlying this cognitive and neurobehavioral toxicity have not yet been clearly elucidated. Nevertheless, multiple candidate mechanisms for chemobrain have been proposed, including individual or cancer-related variables as well as chemotherapy-induced damage or hormonal changes (Ahles and Saykin, 2007). Unfortunately, data directly supporting the proposed mechanisms are limited (Savitz et al., 2006, Seigers and Fardell, 2011).
Concerning individual susceptibility, genetic variability in genes that regulate neural repair and/or plasticity, such as apolipoprotein E (E4) and brain-derived neurothropic factor (BDNF), genetic variability in genes that regulate neurotransmission, such as catechol-O-methyltransferase (COMT), or genetic variability in BBB transporters, as protein P-glycoprotein, might increase the vulnerability of an individual to chemotherapy-induced cognitive changes (Savitz et al., 2006, Hoffmeyer et al., 2000, Nathoo et al., 2003). Recent data from animal studies suggest that very small doses of chemotherapy can cause cell death and reduce cell division in brain structures crucial for cognition, even at doses that do not effectively kill tumor cells (Dietrich et al., 2006). Other individual variables such as age and pretreatment cognitive reserve1 have been associated with post-chemotherapy cognitive decline, as evaluated using processing speed measures (Ahles et al., 2010). Common risk factors for the development of both cancer and neurodegenerative disorders have been also suggested, for example, poor deoxyribonucleic acid (DNA) repair mechanisms (Goode et al., 2002).
Cancer-related variables such as cytokine levels have been also related with cognitive function (Meyers et al., 2005, Seruga et al., 2008, Reichenberg et al., 2001). Cytokine are small proteins secreted by the immune system which have a described negative effect on the hippocampus (Maier and Watkins, 2003).
In addition, chemotherapy treatment can induce changes through DNA damage directly or through increases in oxidative stress, lead to the shortening of telomeres thereby accelerating cell aging, contribute to cytokine deregulation, inhibit hippocampal neurogenesis or reduce brain vascularization and blood flow (Von Zglinicki and Martin-Ruiz, 2005, de Visser et al., 2006, Seigers and Fardell, 2011). All these biological pathways may influence the extent and the recovery of the effect of chemotherapy on cognitive function. Furthermore, chemotherapy agents can be given alone or with other more specific therapies. For example, women with hormone receptor-positive breast cancer are treated with the combination of chemotherapy and hormonal therapy. Changes in levels of hormones, such as estrogen and testosterone associated with menopause or induced by hormonal therapy, have been associated with cognitive decline (Zec and Trivedi, 2002, Castellon et al., 2004). Indeed, chemotherapy might influence hormonal levels or even interact with hormones through a reduction of antioxidant capacity or the ability to maintain telomere length (Lee et al., 2005, Seigers and Fardell, 2011).
Structural and functional neuroimaging has been applied to examine the neural substrate of these cognitive changes in cancer patients. Voxel-based morphometry (VBM) and diffusion-tensor imaging (DTI) are structural neuroimaging techniques that are capable of detecting alterations in gray matter (GM) and white matter (WM) tissue, respectively. Moreover, functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) studies are functional neuroimaging techniques that may contribute to detect differences in brain functioning even when there is no clear structural damage. Hence, neuroimaging studies provide a fine-grained examination of neural changes associated with chemotherapy that are relevant for a better understanding of the natural history of chemotherapy neurotoxic effects. There are a large number of investigations using such techniques in cancer populations. The purpose of this review was to summarize the current literature on the effects of chemotherapy-related cognitive changes with a focus on structural and functional neuroimaging studies.
Section snippets
Methods
The search strategy used to perform this review was designed following two steps. First, we searched the Pubmed, Psycinfo and ISI Web of Knowledge databases looking for review articles devoted to the effects of chemotherapy on the cognitive impairment of cancer patients using neuroimaging techniques. We used the keywords “cancer”, “imaging”, “chemotherapy”, “cognitive impairment” and “neuropsychological effect”, combined using a logical conjunction between all them, excluding the alternation
Structural neuroimaging (MRI) studies
Structural neuroimaging studies include morphological methods that involve manual segmentation of the selected structures (n = 4) (Brown et al., 1995, Brown et al., 1998, Yoshikawa et al., 2005, Ferguson et al., 2007), VBM (n = 6) (Saykin et al., 2003, Inagaki et al., 2007, McDonald et al., 2010, de Ruiter et al., 2012, Koppelmans et al., 2012a, Scherling et al., 2012a) and DTI (n = 4) (Abraham et al., 2008, Deprez et al., 2011, de Ruiter et al., 2012, Deprez et al., 2012). First, we will describe
Limitations
The neuroimaging studies reviewed above exhibited some important limitations. Mainly, there is a huge heterogeneity concerning the experimental methodology. For this reason, since 2011 the International Cancer and Cognitive Task Force (ICCTF) guidelines recommended longitudinal neuropsychological repeated assessment with pretreatment evaluation, as well as two control groups: disease-specific and a healthy control groups (Wefel et al., 2011). The evaluation of a healthy control group is
Conclusions
The review of the neuroimaging studies in cancer and chemotherapy-treated cancer patients revealed both structural and functional differences and yielded several important points.
First, neuropsychological evidence of a subtle pretreatment cognitive impairment in cancer patients, especially in working memory and processing speed, is in agreement with the described widespread decrease in WM volume (Scherling et al., 2012a) and the overactivation of the FPN compared to healthy controls (Cimprich
Acknowledgements
This work was supported by la Fundació Marató-TV3 [Acquired Spinal Cord and Brain Injuries Program (2012–2015) awarded to ARF] and the Catalan Government [Generalitat de Catalunya, 2009 SGR 93 to ARF]. Marta Simó is a recipient of a Rio Hortega research contract (code: CM11/00256) from the Carlos III National Health Institute (Spanish Government).
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