Chemotherapy-related cognitive dysfunction: current animal studies and future directions

R. Seigers 0 1 S. B. Schagen 0 1 O. Van Tellingen 0 1 J. Dietrich 0 1 0 J. Dietrich Department of Neurology, Division of Neuro-Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School , Boston, MA , USA 1 O. Van Tellingen Division of Molecular Biology, The Netherlands Cancer Institute , Amsterdam , The Netherlands Cognitive impairment is a potential long-term side effect of adjuvant chemotherapy that can have a major impact on the quality of life of cancer survivors. There is a growing number of preclinical studies addressing this issue, thereby extending our knowledge of the mechanisms underlying chemotherapy-induced neurotoxicity. In this review, we will summarize the recent advances and important findings presented in these studies. Emerging challenges, such as the development of neuroprotective strategies, and the role of the blood-brain barrier on cognitive impairment will be described and future directions in this field of investigation will be outlined. - Chemotherapy is widely used in patients with systemic cancer but can be harmful to multiple organ systems. The central nervous system (CNS) has generally been considered to be less vulnerable to the toxic effects of chemotherapy. Nevertheless, acute and delayed neurological complications are being identified with increasing frequency. This is likely a consequence of more aggressive and combined treatment modalities as well as overall prolonged patient survival, but also increased awareness of this issue. Cognitive dysfunction has emerged as one of the most puzzling and concerning adverse effects of systemic chemotherapy with a significant impact on patients' quality of life. Therefore, in this review, the effect of systemic chemotherapy (as opposed to intrathecal administration) on cognitive impairment and the underlying neurobiological processes will be discussed. Only a subset of patients receiving systemic chemotherapy will develop cognitive deficits, while others appear to be unaffected. Recent clinical studies suggest, however, that some degree of chemotherapy-induced cognitive impairment occurs in a substantial number of patients, with reported incidences ranging from 15 % to 80 % (Ahles et al. 2010; Koppelmans et al. 2012; Wefel et al. 2010). Many patients may experience such deficits only temporarily during, or after systemic chemotherapy. In other patients, however, symptoms may persist for years, impacting the return to previous levels of academic, occupational or social activities. Common cognitive domains affected by chemotherapy include learning, memory, information processing speed, and executive function (Dietrich et al. 2008; Wefel et al. 2004). Recent imaging studies have demonstrated structural changes in the brain of chemotherapy treated cancer patients when compared with healthy controls, or cancer patients not treated with systemic chemotherapy. Treatment effects on brain structure include volume reduction of both white and grey matter and altered white matter integrity (Wefel and Schagen 2012). The mechanisms underlying chemotherapy-induced neurotoxicity have not been elucidated. However, in recent years, a rapidly growing number of experimental studies in rodent models has increased our understanding of the cell-biological and molecular mechanisms underlying chemotherapy associated CNS toxicity. We here summarize recent advances and important findings from preclinical studies, highlight emerging challenges, and outline future directions in this field of investigation. Animal models of chemotherapy induced neurotoxicity While the exact neurotoxic mechanisms are still elusive, numerous preclinical studies have demonstrated a clear link between chemotherapy and cognitive dysfunction. An increasing body of literature suggests that diverse cytostatic agents can disrupt various neurobiological processes and induce cognitive impairment in animal models. Adverse neurological effects have been observed with virtually all categories of chemotherapeutic agents and biologics, including antimetabolites, DNA cross-linking agents, mitotic inhibitors, antihormonal agents, and molecular-targeted agents (Table 1). Agents explored in more detail with respect to their neurotoxic effects on the CNS include carmustine (BCNU), cisplatin, cyclophosphamide, cytarabine (Ara-C), doxorubicin, 5fluorouracil (5-FU), ifosfamide, lomustine (CCNU), methotrexate (MTX), oxaliplatin, paclitaxel, thioTEPA, topotecan, and vinblastine. Cognitive deficits were observed in tasks that involve hippocampal and frontal network systems, such as Morris water maze learning, novel location recognition, and non-matching to sample learning. In most published studies animals treated with one or more cytostatic agent were compared to control animals. Data from these studies suggest that the degree of neurotoxicity is dependent on the chemotherapeutic agent tested, but also on the animal model and type of test battery used (Seigers and Fardell 2011). A few prospective animal studies were performed, in which the cognition of animals before and after treatment was compared (Liedke et al. 2009; Long et al. 2011; Seigers et al. 2009), and these showed that cytostatic treatment can also impair memory retention. Synergistic neurotoxic effects have been reported by many groups, including by Wincour et al. showing that animals treated with MTX and 5-FU developed impaired learning in spatial memory and (delayed) non-matching-tosample learning in tasks acquired pretreatment, as well as in novel tasks (Winocur et al. 2012). Even when taking the variation in experimental design in animal studies into account, patterns of chemotherapyinduced cognitive impairment in animals seems to correspond to cognitive data of patients (Seigers and Fardell 2011; Wefel et al. 2010). This important correlation has supported the notion that neurobiological research of chemotherapyinduced CNS damage in animal models is able to provide critical insights into the mechanisms of chemotherapyinduced cognitive impairment in patients. Many animal studies explored the cell-biological and metabolic effects of Table 1 Mechanisms affected by chemotherapeutic agents in preclinical in vivo studies Cyclophosphamide, 5-FU, methotrexate Methotrexate Methotrexate Table 1 (continued) 2010; Janelsins et al. 2010; Lau et al. 2009; Lyons et al. 2011a, b; Lyons et al. 2012; Mignone and Weber 2006; Mondie et al. 2010; Mustafa et al. 2008; Nokia et al. 2012; Seigers et al. 2008; Seigers et al. 2009; Seigers et al. 2010a; Wilson and Weber 2013; Yang et al. 2010; Yang et al. 2011; Yang et al. 2012). Using a detailed cell lineage-based approach to test the effects of commonly applied chemotherapeutic agents on mature and immature cell types of the nervous system, it has been shown that neural progenitor cells, which are the direct ancestors of all differentiated cell types of the CNS, and (mature) oligodendrocytes are the most vulnerable cell populations to the effec (...truncated)