Chemotherapy-associated Cognitive Impairment Research Articles

Microglia are implicated in the development of paclitaxel chemotherapy-associated cognitive impairment in female mice

Chemotherapy remains a mainstay in the treatment of many types of cancer even though it is associated with debilitating behavioral side effects referred to as “chemobrain,” including difficulty concentrating and memory impairment. The predominant hypothesis in the field is that systemic inflammation drives these cognitive impairments, although the brain mechanisms by which this occurs remain poorly understood. Here, we hypothesized that microglia are activated by chemotherapy and drive chemotherapy-associated cognitive impairments. To test this hypothesis, we treated female C57BL/6 mice with a clinically-relevant regimen of a common chemotherapeutic, paclitaxel (6 i.p. doses at 30 mg/kg), which impairs memory of an aversive stimulus as assessed via a contextual fear conditioning (CFC) paradigm. Paclitaxel increased the percent area of IBA1 staining in the dentate gyrus of the hippocampus. Moreover, using a machine learning random forest classifier we identified immunohistochemical features of reactive microglia in multiple hippocampal subregions that were distinct between vehicle- and paclitaxel-treated mice. Paclitaxel treatment also increased gene expression of inflammatory cytokines in a microglia-enriched population of cells from mice. Lastly, a selective inhibitor of colony stimulating factor 1 receptor, PLX5622, was employed to deplete microglia and then assess CFC performance following paclitaxel treatment. PLX5622 significantly reduced hippocampal gene expression of paclitaxel-induced proinflammatory cytokines and restored memory, suggesting that microglia play a critical role in the development of chemotherapy-associated neuroinflammation and cognitive impairments. This work provides critical evidence that microglia drive paclitaxel-associated cognitive impairments, a key mechanistic detail for determining preventative and intervention strategies for these burdensome side effects.

Microglia are implicated in the development of chemotherapy-associated cognitive impairment in female mice

Microglia are implicated in the development of chemotherapy-associated cognitive impairment in female mice

Cognitive adverse effects of chemotherapy and immunotherapy: are interventions within reach?

One in three people will be diagnosed with cancer during their lifetime. The community of cancer patients is growing, and several common cancers are becoming increasingly chronic; thus, cancer survivorship is an important part of health care. A large body of research indicates that cancer and cancer therapies are associated with cognitive impairment. This research has mainly concentrated on chemotherapy-associated cognitive impairment but, with the arrival of immunotherapies, the focus is expected to widen and the number of studies investigating the potential cognitive effects of these new therapies is rising. Meanwhile, patients with cognitive impairment and their healthcare providers are eagerly awaiting effective approaches to intervene against the cognitive effects of cancer treatment. In this Review, we take stock of the progress that has been made and discuss the steps that need to be taken to accelerate research into the biology underlying cognitive decline following chemotherapy and immunotherapy and to develop restorative and preventive interventions. We also provide recommendations to clinicians on how to best help patients who are currently experiencing cognitive impairment.

Recent progress in the elucidation of the mechanisms of chemotherapy-induced cognitive impairment.

The term "chemobrain" refers to the cognitive dysfunction that occurs after chemotherapy, and it is also known as chemotherapy-induced cognitive impairment or "chemofog". The aim of this review is to bring together the findings of existing literature on the topic and summarize the current knowledge on the potential mechanisms of chemobrain. According to the reviewed studies, the mechanisms by which chemotherapy could cause chemobrain include disruption of hippocampal cell proliferation and neurogenesis, hormonal changes, increased oxidative stress and reactive oxygen species production, chronic increase in inflammation, and alterations in synaptic plasticity and long-term potentiation. While the effects of inflammation and oxidative stress on neurogenesis and their role in chemotherapy-induced cognitive impairment have been widely studied, the chemotherapy-induced cognitive impairment mechanisms that involve mitochondrial dysfunction, estrogen dysregulation, and increased transglutaminase 2 are still unclear. Further studies on these mechanisms are necessary to understand the effects of chemotherapy at the cellular and molecular level and facilitate the development of preventive and therapeutic strategies against chemotherapy-associated cognitive impairment or chemobrain.

An Evaluation of DNA Methyltransferase 1 (DNMT1) Single Nucleotide Polymorphisms and Chemotherapy-Associated Cognitive Impairment: A Prospective, Longitudinal Study

Strong evidence suggests that genetic variations in DNA methyltransferases (DNMTs) may alter the downstream expression and DNA methylation patterns of neuronal genes and influence cognition. This study investigates the association between a DNMT1 polymorphism, rs2162560, and chemotherapy-associated cognitive impairment (CACI) in a cohort of breast cancer patients. This is a prospective, longitudinal cohort study. From 2011 to 2017, 351 early-stage breast cancer patients receiving chemotherapy were assessed at baseline, the midpoint, and the end of chemotherapy. DNA was extracted from whole blood, and genotyping was performed using Sanger sequencing. Patients’ self-perceived cognitive function and cognitive performance were assessed at three different time points using FACT-Cog (v.3) and a neuropsychological battery, respectively. The association between DNMT1 rs2162560 and cognitive function was evaluated using logistic regression analyses. Overall, 33.3% of the patients reported impairment relative to baseline in one or more cognitive domains. Cognitive impairment was observed in various objective cognitive domains, with incidences ranging from 7.2% to 36.9%. The DNMT1 rs2162560 A allele was observed in 21.8% of patients and this was associated with lower odds of self-reported cognitive decline in the concentration (OR = 0.45, 95% CI: 0.25–0.82, P = 0.01) and functional interference (OR = 0.48, 95% CI: 0.24–0.95, P = 0.03) domains. No significant association was observed between DNMT1 rs2162560 and objective cognitive impairment. This is the first study to show a significant association between the DNMT1 rs2162560 polymorphism and CACI. Our data suggest that epigenetic processes could contribute to CACI, and further studies are needed to validate these findings.

Impact of Adjuvant Anthracycline-Based and Taxane-Based Chemotherapy on Plasma VEGF Levels and Cognitive Function in Breast Cancer Patients: A Longitudinal Study

BackgroundVascular endothelial growth factor (VEGF) has been shown to induce neurogenesis in the brain and yield neuroprotective effects. It is hypothesized that chemotherapy reduces circulating VEGF levels and leads to cognitive decline among patients. This multicenter longitudinal study aimed to evaluate the impact of chemotherapy on VEGF levels and the association between VEGF levels and cognitive function. Patients and MethodsA total of 145 early-stage breast cancer patients were recruited and assessed before chemotherapy (T1), during chemotherapy (T2), and at the end of chemotherapy (T3). At each time point, plasma VEGF levels were assessed using a multiplex immunoassay. Cognitive function was assessed using both Functional Assessment of Cancer Therapy–Cognitive Function, Version 3 (FACT-Cog), and Headminder (a computerized, web-based neuropsychologic battery). ResultsGenerally, we observed higher-than-baseline plasma VEGF levels after the start of chemotherapy (P < .001). Among patients receiving anthracycline-based chemotherapy, the median plasma VEGF levels were significantly higher at T2 (T2: 37.3 pg/mL vs. T1: 21.3 pg/mL; P < .001) and T3 (T3: 35.5 pg/mL vs. T1: 21.3 pg/mL; P < .001) than at baseline. Plasma VEGF levels were not associated with chemotherapy-associated cognitive impairment. ConclusionBreast cancer patients experience an increasing trend in plasma VEGF levels during chemotherapy, and the regimen types may have a differential effect on circulating VEGF levels. Furthermore, changes in plasma VEGF levels during chemotherapy were not associated with cognitive impairment. VEGF may play a minor role in mediating the occurrence of chemotherapy-associated cognitive impairment.

Evaluation of plasma brain-derived neurotrophic factor levels and self-perceived cognitive impairment post-chemotherapy: a longitudinal study

BackgroundPreliminary evidence suggests that changes in plasma brain-derived neurotrophic factor (BDNF) levels may contribute to the occurrence of chemotherapy-associated cognitive impairment (CACI), and a previous study suggested that carriers of the BDNF Met homozygous genotype are protected from CACI.MethodsThis multicenter, prospective cohort study involved chemotherapy-receiving early-stage breast cancer (ESBC) patients. Self-perceived cognitive function was longitudinally assessed using the validated FACT-Cog (ver. 3) across three time points: Prior to chemotherapy (T1), during chemotherapy (T2), and at the end of chemotherapy (T3). Plasma BDNF levels were quantified using enzyme-linked immunosorbent assay. Genotyping was performed using Sanger Sequencing.ResultsA total of 51 chemotherapy-receiving ESBC patients (mean age: 52.6 ± 9.5 years) were recruited, and 11 patients (21.6%) reported subjective cognitive impairment post-chemotherapy. Overall, there was a reduction in median plasma BDNF levels over time (T1: 5423.0 pg/ml; T2: 5313.6 pg/ml; T3: 4050.3 pg/ml; p < 0.01). After adjusting for confounding factors, longitudinal analysis revealed that BDNF levels were associated with self-reported concentration deficit (p = 0.032). Carriers of Val/Val (p = 0.011) and Val/Met (p = 0.003) BDNF genotypes demonstrated a significant reduction in plasma BDNF levels over time; however, plasma BDNF levels were similar across all time points among Met homozygous carriers (p = 0.107).ConclusionThere was a statistically significant change in BDNF levels post-chemotherapy in ESBC patients, and plasma BDNF levels were associated with self-perceived concentration deficit in patients receiving chemotherapy.

A web-based tool to predict chemotherapy-associated cognitive impairment during survivorship.

e21609 Background: Chemotherapy-associated cognitive impairment (CACI) experienced during survivorship can dramatically impair quality of life, particularly among patients receiving treatment with curative intent. We construct a web-based tool to predict the risk of self-perceived CACI at 15 months post-chemotherapy initiation among early stage breast cancer patients, to facilitate screening and early intervention. Methods: We recruited patients receiving chemotherapy for early-stage breast cancer between 2011 and 2014. Subjective cognitive function was assessed using FACT-Cog before, during and at 15 months after initiating chemotherapy. Based on a previously established minimal clinically important difference, an 11-point reduction in FACT-Cog score relative to that at baseline was considered as clinically significant CACI. Factors evaluated as potential predictors of CACI included clinical, laboratory and demographic factors, behavioural symptom and quality of life assessments (EORTC-QLQ-C30). Logistic regression was used to construct a model predicting CACI. Validation was performed on an external cohort recruited between 2015 and 2016. Model discrimination and calibration were evaluated using the receiver operating curve (ROC) and Hosmer-Lemeshow goodness-of-fit, respectively. The model was implemented as a web-based tool. Results: A total of 131 patients were recruited for model development. The model consisted of baseline EORTC-QLQ-C30 fatigue subscale percentage [effect size (95% confidence interval), 5.0% (2.0% to 7.0%), p &lt; 0.001] and the change in FACT-Cog score after 2 cycles of chemotherapy, relative to baseline [-4.0% (-7.0% to -1.0%), p = 0.007]. The model was validated on an external cohort of 33 patients, with an ROC of 0.60, Hosmer-Lemeshow goodness-of-fit statistic of 5.86 (p = 0.44), sensitivity of 57.1% and specificity of 76.9%. The web application is accessible at http://bit.ly/CognitiveRisk Conclusions: A web application to predict CACI risk has been developed and externally validated. The tool facilitates early screening for patients at high risk for CACI and allows timely interventions to prevent or minimize the impact of CACI during survivorship.

A genome-wide association study (GWAS) meta-analysis of chemotherapy-associated cognitive impairment (CACI) in Asian early-stage breast cancer patients (ESBC).

10096 Background: Genetic variations among genes regulating neuronal function, neurotransmission and plasticity may contribute to varying risk of CACI. In order to fully elucidate the complex genetic structure underlying CACI, a GWAS meta-analysis was performed to identify genetic variants associated with CACI among ESBC patients. Methods: A GWAS meta-analysis of two independent cohorts totaling 266 chemotherapy-receiving ESBC patients (mean age: 51.0 ± 9.2 years; 80.8% Chinese) was performed. Patients’ self-perceived cognitive function was assessed using the validated FACT-Cog (v.3). Genome-wide genotyping was performed using the Illumina HumanOmniExpress-24 version 1.1 BeadChips kits. Each beadchip contains over 700,000 genetic markers. Covariates included in the meta-analysis were the first two dimensions of the multi-dimensional scaling. Results: After applying stringent quality control measures and removing four population outliers, data from 546,399 SNPs were available for 84 cases and 170 controls. In the meta-analysis, two SNPs (rs6443264 and rs4686371) exceeded the suggestive threshold of P &lt; 1×10-5 (Table). Following adjustment for the first two MDS dimensions in the meta-analysis, both SNPs remained as top two SNPs with P &lt; 1×10-4. Both rs6443264 and rs4686371 are located in chromosome 3p25 and lie in the intronic regions encoding OGG1 and ARPC4 genes, respectively. Alteration of the OGG1 gene could compromise the functions of downstream neuronal genes, and modification of the ARPC4 gene could affect the formation of the actin-related protein 2/3 complex and impair memory formation. Conclusions: To the best of our knowledge, this is the first GWAS meta-analysis to identify two loci, namely rs6443264 and rs4686371 that are suggestive of genome-wide association with CACI among Asian ESBC patients. [Table: see text]

Impact of TNF-α (rs1800629) and IL-6 (rs1800795) Polymorphisms on Cognitive Impairment in Asian Breast Cancer Patients.

ObjectiveExpression of pro-inflammatory cytokines is influenced by single nucleotide polymorphisms (SNPs) in the promoter regions of the pro-inflammatory cytokine genes, and cytokines are associated with the occurrence of post-chemotherapy cognitive impairment. Hence, the aim of this study was to evaluate the associations between two common pro-inflammatory cytokine gene polymorphisms namely, IL6-174 (rs1800795 G>C) and TNF-308 (rs1800629 G>A), and chemotherapy-associated cognitive impairment (CACI) among Asian early-stage breast cancer patients. In addition, the differential effect of these SNPs on plasma IL-6 and TNF-α levels, and the associations of plasma IL-6 and TNF-α levels with CACI were also assessed.MethodsAsian early-stage breast cancer patients (Stage I to III) receiving chemotherapy were prospectively recruited from two cancer centers in Singapore. Patients' cognitive function was longitudinally assessed using the validated FACT-Cog (ver. 3) and an objective computerized battery, Headminder™ at three-time points. Plasma IL-6 and TNF-α levels were analyzed using the multiplex immunoassay, and genotyping was performed using Sanger sequencing. Regression analyses and generalized estimating equation were utilized for statistical analysis.ResultsA total of 125 patients were included (mean age: 50.3; Chinese: 80.8%; post-menopausal: 48.0%; 68.0% received anthracycline-based chemotherapy). 36.8% patients experienced self-perceived cognitive impairment, detected in memory (32.8%) and attention (34.2%) domains. Patients with higher levels of anxiety (p<0.001) and insomnia (p = 0.003) also reported more self-perceived cognitive impairment. Higher plasma concentrations of IL-6 were associated with greater severity of self-perceived cognitive impairment (p = 0.001). Polymorphisms of cytokine genes were not associated with expression of plasma cytokines.ConclusionPresent findings further contribute to the growing evidence that supports the role of the pro-inflammatory cytokine IL-6 in the occurrence of cognitive impairment post-chemotherapy. However, genetic polymorphism of these cytokines did not play a major role to the cytokine fluctuations as well as cognitive impairment in this cohort. With an increasing evidence to support the cytokine hypothesis, future studies should investigate the role of anti-inflammatory agents in mitigating the cognitive impairment associated with chemotherapy.

DNA methyltransferase 1 (DNMT1) polymorphism and chemotherapy-associated cognitive impairment in early-stage breast cancer patients (ESBC): A prospective, longitudinal study.

10014Background: Epigenetic regulation via methylation plays a crucial role for the functioning and survival of neuronal cells. DNA methyltransferase 1 (DNMT1) is an enzyme to maintain methylation ...

Cognitive Impairment in Survivors of Adolescent and Early Young Adult Onset Non-CNS Cancers: Does Chemotherapy Play a Role?

The development of complex cognitive functions including executive functions occurs during adolescence and early young adulthood. Survivors of cancers diagnosed during adolescence and young adulthood (AYA) may be at specific risk for chemotherapy-associated cognitive impairment; however, little data are available that specifically examine long-term cognitive outcomes in the AYA-onset cancer survivor population. A literature search was conducted between January 1991 to December 2015 using a variety of search terms pertaining to the AYA-onset cancer population and cognitive outcomes. Articles that described cognitive outcomes in AYA-onset cancer survivors without primary or secondary central nervous system lesions diagnosed at ages 14-25 years old were examined and reported. Three articles fulfilled the inclusion criteria. All three evaluated cognitive outcomes in AYA-onset cancer survivors at varying time points after receipt of systemic chemotherapy. Target groups and neuropsychological evaluation techniques differ across studies. All studies reported increased rates of objective or self-reported cognitive impairment in AYA-onset cancer survivors. AYA-onset cancer survivors experience cognitive impairment. Despite the nature of normal adolescent neurodevelopment, chemotherapy exposure during the AYA years may not significantly contribute to cognitive impairment. Chronic cognitive impairment may be associated with chronic complications of cancer therapy. Large-scale standardized, prospective, and longitudinal evaluations of cognitive outcomes specific to AYA-onset cancer survivor population are needed to better understand associated risk factors.

Fluvoxamine alleviates paclitaxel-induced neurotoxicity

Paclitaxel (Px) is an effective chemotherapeutic agent for the treatment of various cancers. However, it is often associated with neurological side effects, including chemotherapy-associated cognitive impairment (CACI), such as “chemobrain”. Previously, we reported that endoplasmic reticulum (ER) stress is involved in Px-induced neurotoxicity, and immunoglobulin heavy chain binding protein (BiP) inducer X (BIX) alleviates Px-induced neurotoxicity. However, BIX has not been used in clinical practice yet. We recently reported that fluvoxamine (Flv) alleviates ER stress via induction of sigma-1 receptor (Sig-1R). The purpose of this study was to investigate whether Flv could alleviate Px-induced neurotoxicity in vitro. SK-N-SH cells were pre-treated for 12h with or without 10μg/ml Flv followed by treatment with 1μM Px with or without co-existence of 10μg/ml Flv for 24h. To investigate the involvement of Sig-1R in alleviation effect on Px-induced neurotoxicity,1μM NE100, an antagonist of Sig-1R, was added for 24h. Neurotoxicity was assessed using the MTS viability assay and ER stress-mediated neurotoxicity was assessed by evaluating the expression of C/EBP homologous protein (CHOP), cleaved caspase 4, and cleaved caspase 3.Pre-treatment with Flv significantly alleviated the induction of CHOP, cleaved caspase 4, and cleaved caspase 3 in SK-N-SH cells. At the same time, pre-treatment with Flv significantly induced Sig-1R in SK-N-SH cells. In addition, viability was significantly higher in Flv-treated cells than in untreated cells, which was reversed by treatment with NE100.Our results suggest that Flv alleviates Px-induced neurotoxicity in part through the induction of Sig-1R. Our findings should contribute to one of the novel approaches for the alleviation of Px-induced neurotoxicity, including chemobrain.

Brain-derived neurotrophic factor genetic polymorphism (rs6265) is protective against chemotherapy-associated cognitive impairment in patients with early-stage breast cancer.

BackgroundBrain-derived neurotrophic factor (BDNF), a neurotrophin that regulates neuronal function and development, is implicated in several neurodegenerative conditions. Preliminary data suggest that a reduction of BDNF concentrations may lead to postchemotherapy cognitive impairment. We hypothesized that a single nucleotide polymorphism (rs6265) of the BDNF gene may predispose patients to cognitive impairment. This study aimed to evaluate the effect of BDNF gene polymorphism on chemotherapy-associated cognitive impairment.MethodsOverall, 145 patients receiving chemotherapy for early-stage breast cancer (mean age: 50.8 ± 8.8 y; 82.1% Chinese) were recruited. Patients' cognitive functions were assessed longitudinally using the validated Functional Assessment of Cancer Therapy–Cognitive Function (v.3) and an objective computerized tool, Headminder. Genotyping was performed using Sanger sequencing. Logistic regression was used to evaluate the association between BDNF Val66Met polymorphism and cognition after adjusting for ethnicity and clinically important covariates.ResultsOf the 145 patients, 54 (37%) reported cognitive impairment postchemotherapy. The Met/Met genotype was associated with statistically significant lower odds of developing cognitive impairment (odds ratio [OR] = 0.26; 95% CI: 0.08–0.92; P = .036). The Met carriers were less likely to experience impairment in the domains of verbal fluency (OR = 0.34; 95% CI: 0.12–0.90; P = .031) and multitasking ability (OR = 0.37; 95% CI: 0.15–0.91; P = .030) compared with the Val/Val homozygote. No associations were observed between Headminder and the BDNF Val66Met polymorphism.ConclusionsThis is the first study to provide evidence that carriers of the BDNF Met allele are protected against chemotherapy-associated cognitive impairment. Further studies are required to validate the findings.

Association of proinflammatory cytokines and chemotherapy-associated cognitive impairment in breast cancer patients: a multi-centered, prospective, cohort study

Existing evidence suggests that proinflammatory cytokines play an intermediary role in postchemotherapy cognitive impairment. This is one of the largest multicentered, cohort studies conducted in Singapore to evaluate the prevalence and proinflammatory biomarkers associated with cognitive impairment in breast cancer patients. Chemotherapy-receiving breast cancer patients (stages I-III) were recruited. Proinflammatory plasma cytokines concentrations [interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, granulocyte-macrophage colony-stimulating factor, interferon-γ and tumor necrosis factor-α] were evaluated at 3 time points (before chemotherapy, 6 and 12 weeks after chemotherapy initiation). The FACT-Cog (version 3) was utilized to evaluate patients' self-perceived cognitive disturbances and a computerized neuropsychological assessment (Headminder) was administered to evaluate patients' memory, attention, response speed and processing speed. Changes of cognition throughout chemotherapy treatment were compared against the baseline. Linear mixed-effects models were applied to test the relationships of clinical variables and cytokine concentrations on self-perceived cognitive disturbances and each objective cognitive domain. Ninety-nine patients were included (age 50.5 ± 8.4 years; 81.8% Chinese; mean duration of education = 10.8 ± 3.3 years). Higher plasma IL-1β was associated with poorer response speed performance (estimate: -0.78; 95% confidence interval (CI) -1.34 to -0.03; P = 0.023), and a higher concentration of IL-4 was associated with better response speed performance (P = 0.022). Higher concentrations of IL-1β and IL-6 were associated with more severe self-perceived cognitive disturbances (P = 0.018 and 0.001, respectively). Patients with higher concentrations of IL-4 also reported less severe cognitive disturbances (P = 0.022). While elevated concentrations of IL-6 and IL-1β were observed in patients with poorer response speed performance and perceived cognitive disturbances, IL-4 may be protective against chemotherapy-associated cognitive impairment. This study is important because cytokines would potentially be mechanistic mediators of chemotherapy-associated cognitive changes.

Evaluation of brain-derived neurotrophic factor (BDNF) genetic polymorphism (rs6265) on chemotherapy-associated cognitive impairment in early-stage breast cancer (ESBC) patients.

9616 Background: BDNF is a neurotrophin that regulates neuronal function and development, which is implicated in several neurodegenerative conditions. There is preliminary data to suggest that the ...

Cytokines as Mediators of Chemotherapy-Associated Cognitive Changes: Current Evidence, Limitations and Directions for Future Research

ObjectivesWhile various clinical and pharmacological determinants for chemotherapy-associated cognitive impairment have been identified, conflicting evidence suggests that cytokines might play an intermediary role. The objective of this systematic review was to evaluate the current evidence pertaining to the associations among chemotherapy, cytokines induction and cognitive impairment in cancer patients.MethodsA literature search with PubMed and SciVerse Scopus was conducted in March 2013 to gather relevant articles and abstracts that fulfilled the inclusion and exclusion criteria. This review included studies that had performed objective and/or subjective cognitive assessments and cytokine measurements on defined populations of cancer patients who received chemotherapy.ResultsHigh methodological heterogeneity existed among the selected studies which differed in cancer populations, subject characteristics, cognitive endpoints, types of cytokines tested and their measurement methods. Weak to moderate correlations were observed between IL-1β, IL-6, TNF-α levels, and different degrees of cognitive impairment. Different types of chemotherapy treatments might lead to varying presentations and severities of cytokine-induced cognitive impairment. Notably, the time concordance between the onset of cytokine induction and occurrence of cognitive impairment was not well elucidated. A number of confounding factors was identified to interfere with the expression levels of cytokines; these confounders included subjects' cancer types, ages, genders, genetics and psychosocial characteristics such as anxiety, depression and fatigue.ConclusionAlthough existing studies observed cognitive impairment and cytokine dysregulation in patients who receive chemotherapy, our results suggest that the intermediary role of cytokines in post-chemotherapy cognitive impairment is still controversial and requires further evaluation. A list of methodological recommendations is proposed to harmonize future studies of this subject matter.

Paclitaxel induces neurotoxicity through endoplasmic reticulum stress

Due to chemotherapy, the majority of breast cancer patients survive, but frequently complain of chemotherapy-associated cognitive impairment. This phenomenon is termed “chemobrain” or “chemofog” in the literature. However, its mechanisms are unclear. The objective of this study was to investigate the mechanisms of paclitaxel (Px)-induced neurotoxicity, with a focus on endoplasmic reticulum (ER) stress.To investigate Px-induced neurotoxicity and ER stress induction, SK-N-SH cells were treated with 1, 10, 50, and 100μM Px for 24h. Neurotoxicity was assessed using MTS viability assays, and ER stress was assessed by evaluating the expression of phosphorylated elF2α (phospho-eIF2α), C/EBP homologous protein (CHOP), and cleaved caspase 4 and caspase 3 (the active form of each caspase). Furthermore, to investigate whether immunoglobulin heavy-chain binding protein (BiP) inducer X (BIX), which induces the molecular chaperone BiP, could attenuate Px-induced neurotoxicity, SK-N-SH cells were pre-treated for 12h with 3.5μM BIX before Px treatment.Neurotoxicity was observed in SK-N-SH cells treated with Px in a dose-dependent manner compared with vehicle control. Furthermore, phospho-eIF2α, CHOP, and activated caspase 4 and caspase 3 were significantly induced in Px-treated cells. In addition, pre-treatment with BIX significantly attenuated the induction of CHOP and activated caspase 4 and caspase 3. The viability of BIX pre-treated cells prior to Px treatment was significantly increased compared with cells that were not treated with BIX. Our results suggest that Px induces neurotoxicity in part through activating the ER stress response. Our findings should contribute to novel approaches regarding the mechanism of Px-induced neurotoxicity, including chemobrain.

Cancer ‘survivor-care’: II. Disruption of prefrontal brain activation top-down control of working memory capacity as possible mechanism for chemo-fog/brain (chemotherapy-associated cognitive impairment)

Cancer chemotherapy-associated cognitive impairments (termed 'chemo-fog' or 'chemo-brain'), particularly in memory, have been self-reported or identified in cancer survivors previously treated with chemotherapy. Although a variety of deficits have been detected, a consistent theme is a detriment in visuospatial working memory. The parietal cortex, a major site of storage of such memory, is implicated in chemotherapy-induced damage. However, if the findings of two recent publications are combined, the (pre)frontal cortex might be an equally viable target. Two recent studies, one postulating a mechanism for 'top-down control' of working memory capacity and another visualizing chemotherapy-induced alterations in brain activation during working memory processing, are reviewed and integrated. A computational model and the proposal that the prefrontal cortex plays a role in working memory via top-down control of parietal working memory capacity is consistent with a recent demonstration of decreased frontal hyperactivation following chemotherapy. Chemotherapy-associated impairment of visuospatial working memory might include the (pre)frontal cortex in addition to the parietal cortex. This provides new opportunity for basic science and clinical investigation.

Establishing a model for assessing DNA damage in murine brain cells as a molecular marker of chemotherapy-associated cognitive impairment

AimsChemotherapy-associated cognitive impairment often follows cancer chemotherapy. We explored chemotherapy-induced DNA damage in the brain cells of mice treated with 5-fluorouracil (5FU), an antineoplastic agent, to correlate the extent of DNA damage to behavioral functioning in an autoshaping-operant mouse model of chemotherapy-induced learning and memory deficits (Foley et al., 2008). Main methodsMale, Swiss-Webster mice were injected once with saline or 75mg/kg 5FU at 0, 12, and 24h and weighed every 24h. Twenty-four h after the last injection, the mice were tested in a two-day acquisition and the retention of a novel response task for food reinforcement. Murine brain cells were analyzed for the presence of single- and double-strand DNA breaks by the single cell gel electrophoresis assay (the Comet assay). Key findingsWe detected significant differences (p<0.0001) for all DNA damage characteristics (DNA “comet” tail shape, migration pattern, tail moment and olive moments) between control mice cohort and 5FU-treated mice cohort: tail length – 119 vs. 153; tail moment – 101 vs. 136; olive moment – 60 vs. 82, correspondingly. We found a positive correlation between increased response rates (r=0.52, p<0.05) and increased rate of errors (r=0.51, p<0.05), and DNA damage on day 1. For all 15 mice (saline-treated and 5FU-treated mice), we found negative correlations between DNA damage and weight (r=−0.75, p<0.02). SignificanceOur results indicate that chemotherapy-induced DNA damage changes the physiological status of the brain cells and may provide insights to the mechanisms for cognitive impairment after cancer chemotherapy.