Neurobiological basis of chemotherapy-induced cognitive impairment : a review of rodent research

For some cancer survivors chemotherapy treatment is associated with lasting cognitive impairment, long after treatment cessation. Several candidate mechanisms have been suggested, yet clinical research has been unable to clearly tease apart these hypotheses. Rodent research has allowed a systematic study of these underlying mechanisms in the absence of potential patient confounds. Herein, this research is reviewed with emphasis on the role of the blood-brain barrier, neurogenesis, oxidative stress, white matter, immune system/(neuro) inflammation, HPA axis, blood flow, and cancer in chemotherapy-induced cognitive impairment. Furthermore, potential pharmacotherapy and behavioral intervention strategies are reviewed. This paper ends with methodological considerations in study of chemotherapy and cognition.13 page(s

Commentary: “Neuropsychological Assessment of Individuals with Brain Tumor: Comparison of Approaches Used in the Classification of Impairment”

A commentary on "Neuropsychological assessment of individuals with brain tumor: comparison of approaches used in the classification of impairment" by Dwan TM, Ownsworth T, Chambers S, Walker DG, Shum DHK. Front Oncol (2015) 5:56. doi: 10.3389/fonc.2015.000562 page(s

The Short and long term effects of docetaxel chemotherapy on rodent object recognition and spatial reference memory

Aims: Previous animal studies have examined the potential for cytostatic drugs to induce learning and memory deficits in laboratory animals but, to date, there is no pre-clinical evidence that taxanes have the potential to cause cognitive impairment. Therefore our aim was to explore the short- and long-term cognitive effects of different dosing schedules of the taxane docetaxel (DTX) on laboratory rodents. Main methods: Healthy male hooded Wistar rats were treated with DTX (6 mg/kg, 10 mg/kg) or physiological saline (control), once a week for 3 weeks (Experiment 1) or once only (10 mg/kg; Experiment 2). Cognitive function was assessed using the novel object recognition (NOR) task and spatial water maze (WM) task 1 to 3 weeks after treatment and again 4 months after treatment. Key findings: Shortly after DTX treatment, rats perform poorly on NOR regardless of treatment regimen. Treatment with a single injection of 10 mg/kg DTX does not appear to induce sustained deficits in object recognition or peripheral neuropathy. Significance: Overall these findings show that treatment with the taxane DTX in the absence of cancer and other anti-cancer treatments causes cognitive impairment in healthy rodents.9 page(s

Single high dose treatment with methotrexate causes long-lasting cognitive dysfunction in laboratory rodents

Clinical studies have suggested that cognitive impairment due to chemotherapy persists long after treatment cessation. While animal studies have similarly found impairments in cognition due to chemotherapy, these studies are limited as they only assess the acute or extremely short-term effects of chemotherapy on cognition (e.g. within 1 month of treatment). Male hooded Wistar rats (N = 22) received either a high dose of methotrexate (MTX: 250 mg/kg i.p.) or physiological saline. Cognitive performance was evaluated acutely at 2 weeks, and up to 8 months post injection using the Morris water maze, Novel object recognition task, and an instrumental go/no-go task to assess discrimination learning. MTX-treated rats displayed impaired novel object recognition compared to controls at 11, 95, and 255 days after treatment. MTX rats were able to learn the hidden spatial location of a platform 22 days after treatment. When tested again after a 95-day retention interval, MTX rats showed impaired spatial memory compared to controls, but were subsequently able to re-learn the task. Finally, MTX-treated rats showed considerable difficulty learning to inhibit their behaviour in an instrumental discrimination task. These results show that chemotherapy produces persistent but subtle cognitive deficits in laboratory rodents that vary with time post treatment.7 page(s

Fear of cancer recurrence : an overview and Australian perspective

Fear of cancer recurrence is broadly defined as the fear or worry that cancer could return or progress in the same place or another part of the body. It is frequently reported as an unmet need by cancer survivors, and does not appear to diminish with time since diagnosis and treatment completion. Fear of cancer recurrence is almost universal among cancer survivors, and those experiencing high levels of fear of cancer recurrence experience difficulties moving on with life after diagnosis and treatment, and have poorer quality of life. It is a prevalent and persistent issue for cancer survivors, with significant costs for the individual, family and society. Those who are younger have greater symptom burden and greater psychological distress are likely to have higher fear of cancer recurrence. Few intervention studies have been reported in the literature to date to guide health service provision. However, several studies are currently underway in Australia to develop empirically tested theory-driven interventions.6 page(s

The Sum of all fears : conceptual challenges with measuring fear of cancer recurrence [commentary]

Fear of cancer recurrence (FCR) is increasingly recognised as a major concern for people with cancer once active treatment is completed. Several instruments have been designed to assess FCR; however, no gold standard has emerged. Many instruments conceptualise FCR as a multidimensional construct. However, this potentially conflates FCR as an outcome with its antecedents and consequences. This is problematic when an aggregate of distinct dimensions is calculated, as is commonly recommended. For example, the total score on the Fear of Cancer Recurrence Inventory is an aggregate of items from seven sub-scales: triggers, severity, psychological distress, coping strategies, functioning impairments, insight and reassurance. Similarly, the total score on the Fear of Progression Questionnaire is an aggregate of affective reaction, partnership/family, work and loss of autonomy. Arguably, the severity and affective reaction domains represent fear, and the other sub-scales represent related concepts, rather than “dimensions” of FCR. The total score represents a combination of concepts whose meaning is unclear. The same total score could be produced by patients with very different experiences, and patients with the same level of fear could have very different total scores. Therefore, we argue that although the level of FCR may be determined by a complex network of antecedents and modifiers and have variable consequences, FCR itself may be a simple concept, which can be assessed using a smaller number of items. Conceptual clarity in its research infancy should prevent FCR becoming a construct that is vaguely operationalised and interpreted.3 page(s

The Chemotherapy agent oxaliplatin impairs the renewal of fear to an extinguished conditioned stimulus in rats

Recent evidence has shown that diverse chemotherapy agents can induce cognitive impairments and neurotoxic damage to the central nervous system. Oxaliplatin (OXP), a platinum compound, has been linked with acute and chronic peripheral neuropathies. This study explored the cognitive impacts of OXP in the rat with a fear conditioning procedure. 10 days prior to conditioning and testing, rats received an intraperitoneal injection of OXP (12 mg/kg). On the first day of conditioning, the rats were conditioned to two CSs (CS-ren and CS-ext) in one set of chambers (context A). They then received three tests on separate days. First, the rats were assessed for contextual fear conditioning in context A. Next, the CSs were presented 20 times in a new context (B) until fear conditioning had extinguished. Finally, one of the CSs (CS-ext) was tested again in the extinction context (B), and the other (CS-ren) presented in a new context (C). Results showed that OXP had no effect on the ability of rats to express fear to the conditioning context (A), or on the expression and extinction of conditioned fear to either CS when presented in a second context (B). However, the administration of OXP did impair the ability of rats to renew levels of conditioned fear to CS-ren when this CS was presented in a novel context (C) following extinction. This profile of impairment is consistent with hippocampal damage, and may also involve frontal cortical, amygdalar and thalamic regions important for context discrimination and the contextual modulation of behaviour.5 page(s

The Long-term impact of oxaliplatin chemotherapy on rodent cognition and peripheral neuropathy

Chemotherapy treatment is associated with cognitive dysfunction in cancer survivors after treatment completion. The duration of these impairments is unclear. Therefore this paper aims to evaluate the lasting impact of varying doses of the chemotherapy oxaliplatin (OX) on cognition and peripheral neuropathy. In Experiment 1 rats were treated once a week for 3 weeks with either physiological saline (control) or 6. mg/kg OX i.p. and were assessed for peripheral neuropathy, using von Frey filaments, and cognitive function, using novel object and location recognition, up to 2 weeks after treatment completion. For Experiment 2 rats received 3 weekly i.p. injections of either physiological saline (control), 0.6. mg/kg, 2. mg/kg or 6. mg/kg OX and assessed for peripheral neuropathy and cognitive function up to 11 months after treatment completion. Systemic OX treatment induced lasting effects on cognitive function at 11 months after treatment, and peripheral neuropathy at 1 month after treatment and these were dose dependent; higher doses of OX resulted in worse cognitive outcomes and more severe peripheral neuropathy.9 page(s

Cognitive impairments caused by oxaliplatin and 5-fluorouracil chemotherapy are ameliorated by physical activity

Rationale: Studies in women with breast cancer, and in animal models, have demonstrated that chemotherapy can have a negative impact on cognitive function. Which chemotherapy agents cause problems with cognition and the aetiology of the impairment is unknown. Furthermore, there is no proven treatment. Objectives: This study aimed to evaluate the effects of 5-fluorouracil (5FU) and oxaliplatin (OX) chemotherapy agents commonly used to treat colorectal cancer on cognition in laboratory rodents. Furthermore, we assessed physical activity as a potential remedy for the observed chemotherapy-induced cognitive deficits. Results: In rodents, treatment with 5FU and OX alone impairs memory as measured by novel object recognition. But combined treatment appears to have greater detrimental effects on hippocampal-dependent tasks, contextual fear recall and spatial reference memory (water maze), yet had no effect on cued fear recall, a non-hippocampal task. These impairments were prevented by 4 weeks of wheel running overnight after 5FU/OX treatment. We found a significant interaction between chemotherapy and exercise: rats receiving both 5FU/OX and exercise had improved cognition relative to non-exercising 5FU/OX rats on novel object recognition and spatial reference memory. Conclusions: The combination 5FU/OX had a significant impact on cognition. However, rats treated with 5FU/OX that exercised post chemotherapy had improved cognition relative to non-exercising rats. This suggests that physical activity may prove useful in ameliorating the cognitive impairments induced by 5FU/OX.11 page(s

Simplifying the assessment of cancer information overload : a comment on Jensen et al. (2014) [letter to the editor]

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