Chemobrain Research Articles

Neural correlates of working memory function in pediatric cancer survivors treated with chemotherapy: an fMRI study.

The goal of this study is to investigate the neural correlates of working memory function associated with chemotherapy in pediatric cancer survivors using event-related functional MRI (fMRI) analysis. Fifteen pediatric cancer survivors treated with chemotherapy and 15 healthy controls were studied. Blood oxygenation level dependent (BOLD) fMRI was acquired. A visual n-back task was used to test working memory function during the fMRI scan. Responses were recorded via an MRI compatible button box for analysis. fMRI scans were analyzed using statistical parametric mapping software. All statistics were corrected for multiple comparisons by false discovery rate, with p < 0.05 as significance. Patients however gave more incorrect responses (p < 0.05), more no responses (p < 0.05), and longer response times (p < 0.05) compared with healthy controls. Correct responses generated significantly lower BOLD responses in the posterior cingulate for pediatric cancer survivors compared with controls (p < 0.05). Incorrect responses generated significantly greater BOLD responses in the angular gyrus in survivors (p < 0.05), and no response trials generated greater BOLD responses within the superior parietal lobule (p < 0.05) compared with controls. Working memory impairment appears to be due to an inability to manipulate information and to retrieve information from memory. The ability to delineate the affected neural circuits associated with chemotherapy-induced cognitive impairment could inform treatment strategies, identify patients at high risk of developing cognitive deficits, and pre-emptively tailor behavioral enrichment to overcome specific cognitive deficits.

Astrocytes rescue neuronal health after cisplatin treatment through mitochondrial transfer

Neurodegenerative disorders, including chemotherapy-induced cognitive impairment, are associated with neuronal mitochondrial dysfunction. Cisplatin, a commonly used chemotherapeutic, induces neuronal mitochondrial dysfunction in vivo and in vitro. Astrocytes are key players in supporting neuronal development, synaptogenesis, axonal growth, metabolism and, potentially mitochondrial health. We tested the hypothesis that astrocytes transfer healthy mitochondria to neurons after cisplatin treatment to restore neuronal health.We used an in vitro system in which astrocytes containing mito-mCherry-labeled mitochondria were co-cultured with primary cortical neurons damaged by cisplatin. Culture of primary cortical neurons with cisplatin reduced neuronal survival and depolarized neuronal mitochondrial membrane potential. Cisplatin induced abnormalities in neuronal calcium dynamics that were characterized by increased resting calcium levels, reduced calcium responses to stimulation with KCl, and slower calcium clearance. The same dose of cisplatin that caused neuronal damage did not affect astrocyte survival or astrocytic mitochondrial respiration. Co-culture of cisplatin-treated neurons with astrocytes increased neuronal survival, restored neuronal mitochondrial membrane potential, and normalized neuronal calcium dynamics especially in neurons that had received mitochondria from astrocytes which underlines the importance of mitochondrial transfer. These beneficial effects of astrocytes were associated with transfer of mitochondria from astrocytes to cisplatin-treated neurons. We show that siRNA-mediated knockdown of the Rho-GTPase Miro-1 in astrocytes reduced mitochondrial transfer from astrocytes to neurons and prevented the normalization of neuronal calcium dynamics.In conclusion, we showed that transfer of mitochondria from astrocytes to neurons rescues neurons from the damage induced by cisplatin treatment. Astrocytes are far more resistant to cisplatin than cortical neurons. We propose that transfer of functional mitochondria from astrocytes to neurons is an important repair mechanism to protect the vulnerable cortical neurons against the toxic effects of cisplatin.

Functional connectome biotypes of chemotherapy-related cognitive impairment.

Cancer-related cognitive impairment (CRCI) is a common neurotoxicity among patients with breast and other cancers. Neuroimaging studies have demonstrated measurable biomarkers of CRCI but have largely neglected the potential heterogeneity of the syndrome. We used retrospective functional MRI data from 80 chemotherapy-treated breast cancer survivors to examine neurophysiologic subtypes or "biotypes" of CRCI. The breast cancer group consisted of training (N = 57) and validation (N = 23) samples. An unsupervised clustering approach using connectomes from the training sample identified three distinct biotypes. Cognitive performance (p < 0.05, corrected) and regional connectome organization (p < 0.001, corrected) differed significantly between the biotypes and also from 103 healthy female controls. We then built a random forest classifier using connectome features to distinguish between the biotypes (accuracy = 91%) and applied this to the validation sample to predict biotype assignment. Cognitive performance (p < 0.05, corrected) and regional connectome organization (p < 0.005, corrected) differed significantly between the predicted biotypes and healthy controls. Biotypes were also characterized by divergent clinical and demographic factors as well as patient reported outcomes. Neurophysiologic biotypes may help characterize the heterogeneity associated with CRCI in a data-driven manner based on neuroimaging biomarkers. Our novel findings provide a foundation for detecting potential risk and resilience factors that warrant further study. With further investigation, biotypes might be used to personalize assessments of and interventions for CRCI.

Systematic review of cognitive sequelae of non-central nervous system cancer and cancer therapy.

The aim of this review is to provide an updated overview of chemotherapy-related cognitive impairment (CRCI) in patients with cancer outside central nervous system (CNS), its incidence and prevalence, the cognitive pattern in neuropsychological studies, neuroimaging findings, and the relationship between chemobrain and aging. Methodological limitations of studies are also discussed. This review was guided by the PRISMA statement. The MEDLINE and Scopus databases were employed to search articles about CRCI in non-CNS cancer patients published from January 2004 to September 2019. Two types of research were reviewed: prospective studies addressing the effects of chemotherapy on cognition and systematic reviews about factors related with CRCI, also as neuroimaging findings and current available treatments. Fifty-nine studies meeting the criteria were analyzed: 47 were longitudinal studies on cancer and cognition and 12 were reviews on risk factors, neuroimaging, and treatment. The majority of studies find cognitive impairment in patients with cancer treated with chemotherapy. The body of the literature on breast cancer is the most abundant, but there are also studies on colorectal, testicular, and lung cancer. Neuroimaging studies show changes in structure and activation in patients undergoing chemotherapy. Non-pharmacological treatment is effective for improving cognition and quality of life. The occurrence of CRCI during the course of treatment in people with different types of cancer is frequent. Some risk factors have been identified, but CRCI is a complex phenomenon, with mediating factors related to cancer and treatment and moderating factors related with lifestyle and health. This review highlights the importance of recognizing that this cognitive dysfunction is frequent, mild to moderate in nature but with great impact on quality of life.

The Mystery of Chemotherapy Brain: Kynurenines, Tubulin and Biophoton Release.

The majority of patients receiving chemotherapy experience post-chemotherapy cognitive impairment, sometimes referred to as "chemo brain" or "chemo fog." The cognitive impairment associated with this syndrome can be severe, and can sometimes last for many years after therapy discontinuation. Despite extensive investigations, its etiology is unknown. We argue that chemo brain results from damage to tubulin within microtubules. This damage can occur directly from tubulin inhibitors such as taxanes, epothilones or vinca alkaloids. Other chemotherapies stimulate increased mitochondrial activity and biophoton release. This results in abnormal tryptophan metabolism and excess production of neurotoxic kynurenines, which, in turn, damage microtubules.

Neuroplasticity-Based Cognitive Remediation for Chemotherapy-Related Cognitive Impairment

Neuroplasticity-Based Cognitive Remediation for Chemotherapy-Related Cognitive Impairment

Cortical Brain Age from Pre-treatment to Post-chemotherapy in Patients with Breast Cancer.

Chemotherapy-related cognitive impairment and associated brain changes may reflect accelerated brain aging; however, empirical evidence for this theory is limited. The purpose of this study was to measure brain aging in newly diagnosed patients with breast cancer treated with chemotherapy (n = 43) and compare its longitudinal change to that of controls (n = 50). Brain age indices, derived from cortical measures, were compared between women with breast cancer and matched healthy controls across 3 timepoints (time 1: pre-surgery, time 2: 1month following chemotherapy completion, and time 3: 1-year post-chemotherapy). The breast cancer group showed a significant decrease in cortical thickness across the 3 timepoints (p < .001) and a trend towards significant increase in predicted brain age especially from pre-treatment (time 1) to post-chemotherapy (time 2) compared to controls (p = 0.08). Greater increase in predicted brain age was related to several clinical factors (HER-2 status, surgery type, and history of neoadjuvant chemotherapy) and greater decrease in cortical thickness was associated with greater decrease in performance on a verbal learning task from time 1 to time 3 (r = - 0.48, p < .01). This study demonstrated evidence of increased cortical brain aging in middle-aged patients with breast cancer following chemotherapy treatment that was associated with decreased verbal memory performance.

Neuron-specific deletion of VEGF or its receptor Flk-1 impairs recognition memory

Vascular endothelial growth factor (VEGF, also known as VEGF-A) is a pleiotropic factor which is expressed by neurons, astrocytes and perivascular macrophages, as well as endothelial cells, in the brain. Recently, VEGF signaling has been implicated in learning and memory, and several clinical and preclinical studies demonstrate that VEGF inhibitors induce cognitive impairment. However, the role of endogenous neuronal VEGF signaling in recognition memory remains unclear. Recently, we have developed mice with forebrain excitatory neuron-specific deletion of VEGF or its receptor, fetal liver kinase 1 (Flk-1) by crossing Camk2a-Cre mice with Vegfaflox/flox and Flk-1flox/flox mice, respectively. Using these conditional knockout mice, the present study addressed the influence of forebrain excitatory neuron-specific deletion of VEGF or Flk-1 on recognition memory in the novel object recognition test. The results show that both short-term (2 h) and long-term (24 h) recognition memory are impaired by neuron-specific deletion of either Flk-1 or VEGF. These findings indicate the physiological importance of endogenous neuronal VEGF-Flk-1 signaling in recognition memory. In addition, the current results also suggest that the impairment of neuronal VEGF-Flk-1 signaling can be a cause of anti-VEGF chemotherapy-induced cognitive impairment.

Managing Cancer and Living Meaningfully (CALM) Intervention on Chemotherapy-Related Cognitive Impairment in Breast Cancer Survivors.

Objective: To evaluate the effectiveness and feasibility of Managing Cancer and Living Meaningfully (CALM), which is used to reduce chemotherapy-related cognitive impairment (CRCI), relieve psychological distress, and improve quality of life (QOL) in Chinese breast cancer survivors (BCs). Methods: Seventy-four BCs were enrolled in this study. All patients were randomly assigned to either the CALM group or the care as usual (CAU) group. All patients were evaluated by the Functional Assessment of Cancer Therapy–Cognitive Function (FACT-Cog), Distress Thermometer (DT), and the Functional Assessment of Cancer Therapy–Breast (FACT-B) before and after CALM or CAU application to BCs with CRCI. We compared the differences in all these scores between the CALM group and the control group and analyzed the correlation between cognitive function and QOL. Results: Compared with the CAU group, the performance of the CALM group on the FACT-Cog, DT, and FACT-B showed significant differences before and after CALM (t = −18.909, −5.180, −32.421, P = .000, .000, .000, respectively). Finally, there was a positive correlation between cognitive function and QOL in breast cancer patients before (r = 0.579, P = .000) and after (r = 0.797, P = .000) treatment. Conclusions: The present results indicated that CALM has salutary effects on the improvement of cognitive impairment and QOL and relieves psychological distress in breast cancer patients, which may be due to a positive correlation between psychological distress and cognitive function or QOL.

Neurophysiologic and ophthalmic markers of chemotherapy-related cognitive impairment in patients diagnosed with hematologic cancer: A feasibility study

BackgroundBiomarkers of chemotherapy-related cognitive impairment (CRCI) in hematologic cancer are understudied and underdeveloped. We evaluated the feasibility of using ophthalmic and neurophysiologic markers to assess CRCI in hematologic cancer. MethodsHematologic cancer patients either receiving (Ctx+) or not receiving (Ctx−) chemotherapy were recruited from a tertiary medical center. Demographically-matched healthy controls (HC) were also recruited. Ctx+ participants completed the following study visits: (1) after diagnosis but prior to chemotherapy (baseline); (2) after one treatment cycle (one-month post-baseline); and (3) after three treatment cycles (three-months post-baseline). Comparison subjects completed assessments at similar intervals. Participants completed: (1) neuropsychological assessments of attention and executive function; (2) neurophysiologic assessments of control over spatial attention and working memory; and (3) ophthalmic assessments of contrast sensitivity and optical coherence tomography (OCT). ResultsWe enrolled 45 participants (15 per group), and 30 participants (Ctx+ = 8; Ctx− = 10; HC = 12) completed all study visits. Ctx+ participants performed worse than HC participants on neuropsychological measures of attention and executive function. Both Ctx+ and Ctx− participants showed changes in neurophysiologic measures of control over spatial attention that differed from HC participants. Ctx+ participants showed chemotherapy-related declines in contrast sensitivity that were predicted by OCT retinal nerve fiber layer thickness (RNFL) changes. Changes in neurophysiologic measures of control over spatial attention were also predicted by OCT RNFL changes. ConclusionWe demonstrated the feasibility of using ophthalmic and neurophysiologic markers as rapid and non-invasive measures that may be useful for tracking CRCI in hematologic cancer.

Cognitive impairment after cytotoxic chemotherapy.

Neurotoxicity is a frequent side effect of cytotoxic chemotherapy and affects a large number of patients. Despite the high medical need, few research efforts have addressed the impact of cytotoxic agents on cognition (ie, postchemotherapy cognitive impairment; PCCI). One unsolved question is whether individual cytotoxic drugs have differential effects on cognition. We thus examine the current state of research regarding PCCI. Neurological symptoms after targeted therapies and immunotherapies are not part of this review. A literature search was conducted in the PubMed database, and 1215 articles were reviewed for predefined inclusion and exclusion criteria. Thirty articles were included in the systematic review. Twenty-five of the included studies report significant cognitive impairment. Of these, 21 studies investigated patients with breast cancer. Patients mainly received combinations of 5-fluorouracil, epirubicin, cyclophosphamide, doxorubicin, and taxanes (FEC/FEC-T). Five studies found no significant cognitive impairment in chemotherapy patients. Of these, 2 studies investigated patients with colon cancer receiving 5-fluorouracil and oxaliplatin (FOLFOX). Independent risk factors for PCCI were patient age, mood alterations, cognitive reserve, and the presence of apolipoprotein E e4 alleles. There is evidence that certain chemotherapy regimens cause PCCI more frequently than others as evidenced by 21 out of 23 studies in breast cancer patients (mainly FEC-T), whereas 2 out of 3 studies with colon cancer patients (FOLFOX) did not observe significant changes. Further studies are needed defining patient cohorts by treatment protocol in addition to cancer type to elucidate the effects of individual cytotoxic drugs on cognitive functions.

Emerging mechanistic underpinnings and therapeutic targets for chemotherapy-related cognitive impairment.

Modern innovations in cancer therapy have dramatically increased the number of cancer survivors. An unfortunately frequent side-effect of cancer treatment is enduring neurological impairment. Persistent deficits in attention, concentration, memory, and speed of information processing afflict a substantial fraction of cancer survivors following completion of these life-saving therapies. Here, we highlight chemotherapy-related cognitive impairment (CRCI) and discuss the current understanding of mechanisms underlying CRCI. New studies emphasize the deleterious impact of chemotherapeutic agents on glial-glial and neuron-glial interactions that shape the form, function and plasticity of the central nervous system. An emerging theme in cancer therapy-related cognitive impairment is therapy-induced microglial activation and consequent dysfunction of both neural precursor cells and mature neural cell types. Recent work has highlighted the complexity of dysregulated intercellular interactions involving oligodendrocyte lineage cells, microglia, astrocytes, and neurons following exposure to traditional cancer therapies such as methotrexate. This new understanding of the mechanistic underpinnings of CRCI has elucidated potential therapeutic interventions, including colony-stimulating factor 1 receptor inhibition, TrkB agonism, and aerobic exercise. Traditional cancer therapies induce lasting alterations to multiple neural cell types. Therapy-induced microglial activation is a critical component of the cause of CRCI, contributing to dysregulation of numerous processes of neural plasticity. Therapeutic targeting of microglial activation or the consequent dysregulation of neural plasticity mechanisms are emerging.

Long-Term Clinical and Neuronuclear Imaging Sequelae of Cancer Therapy, Trauma, and Brain Injury.

Neuronuclear imaging has been used for several decades in the study of primary neurodegenerative conditions, such as dementia and parkinsonian syndromes, both for research and for clinical purposes. There has been a relative paucity of applications of neuronuclear imaging to evaluate nonneurodegenerative conditions that can also have long-term effects on cognition and function. This article summarizes clinical and imaging aspects of 3 such conditions that have garnered considerable attention in recent years: cancer- and chemotherapy-related cognitive impairment, posttraumatic stress disorder, and traumatic brain injury. Further, we describe current research using neuroimaging tools aimed to better understand the relationships between the clinical presentations and brain structure and function in these conditions.

Protective Effects of ACY-1215 Against Chemotherapy-Related Cognitive Impairment and Brain Damage in Mice.

Chemotherapy-related cognitive impairment (CRCI) is a potential long-term side effect during cancer treatment. There are currently no effective treatments for CRCI. Reduction or inhibition of histone deacetylase 6 (HDAC6) has been considered a possible therapeutic strategy for cognitive deficits. HDAC6 inhibition recently has been shown to reverse chemotherapy-induced peripheral neuropathy effectively. In the present study, we examined the effect of HDAC6 inhibitor ACY-1215 (Ricolinostat) on cisplatin-induced brain damage and cognitive deficits in mice. Our results showed that ACY-1215 ameliorated behavioral deficits and dendritic spine loss and increased synaptic density in cisplatin-treated mice. Mechanistically, HDAC6 inhibitor ACY-1215 enhanced α-tubulin acetylation in the hippocampus of cisplatin-treated mice. Furthermore, ACY-1215 recovered cisplatin-induced impaired mitochondrial transport and mitochondrial dysfunction in the hippocampus. Our results suggest that inhibition of HDAC6 improves established cisplatin-induced cognitive deficits by the restoration of mitochondrial and synaptic impairments. These results offer prospective approaches for CRCI, especially because ACY1215 currently serves as an add-on cancer therapy during clinical trials.

The Effects of Doxorubicin-based Chemotherapy and Omega-3 Supplementation on Mouse Brain Lipids.

Chemotherapy-induced cognitive impairment affects ~30% of breast cancer survivors, but the effects on how chemotherapy impacts brain lipids, and how omega-3 polyunsaturated fatty acid supplementation may confer protection, is unknown. Ovariectomized mice were randomized to two rounds of injections of doxorubicin + cyclophosphamide or vehicle after consuming a diet supplemented with 2% or 0% EPA+DHA, and sacrificed 4, 7, and 14 days after the last injection (study 1, n = 120) or sacrificed 10 days after the last injection (study 2, n = 40). Study 1 whole brain samples were extracted and analyzed by UHPLC-MS/MS to quantify specialized pro-resolving mediators (SPMs). Lipidomics analyses were performed on hippocampal extracts from study 2 to determine changes in the brain lipidome. Study 1 results: only resolvin D1 was present in all samples, but no differences in concentration were observed (P > 0.05). Study 2 results: chemotherapy was positively correlated with omega-9 fatty acids, and EPA+DHA supplementation helped to maintain levels of plasmalogens. No statistically significant chemotherapy*diet effect was observed. Results demonstrate a limited role of SPMs in the brain post-chemotherapy, but a significant alteration of hippocampal lipids previously associated with other models of cognitive impairment (i.e., Alzheimer’s and Parkinson’s disease).

Individualized Piano Instruction for Improving Cognition in Breast Cancer Survivors.

To evaluate the use of individualized piano instruction (IPI) for improving cognition among breast cancer survivors. Six participants were included in an eight-week piano program with three data collection time points at baseline, midpoint, and postintervention. Participants were recruited from the breast cancer clinic of a university cancer center in South Florida. Neurocognitive, psychosocial, and self-report assessments were conducted to determine potential benefits and program feasibility, including the NIH Toolbox® Cognition Battery, the Functional Assessment of Cancer Therapy (FACT)-Cognitive Function, the FACT-Breast, the Patient Health Questionnaire-9, the Generalized Anxiety Disorder-7, and a participant questionnaire. Results related to potential benefits suggest that IPI may significantly improve overall cognition in breast cancer survivors, with fluid cognition showing improvement. In addition, IPI may improve quality of life and self-reported measures of depression and anxiety, with large to moderate effect sizes, respectively. Nurses should explore different treatment options for chemotherapy-related cognitive impairment and consider including IPI in survivorship care plans.

Chemotherapy-induced cognitive impairment in hematological malignancies

ObjectivesChemotherapy-induced cognitive impairment (CICI) is one of the most prominent side effects as it negatively impacts activities of daily life of the affected role. These problems can range from subtle to severe and last for months or years after discourse. As cognition is an important predictor of survival in patients with hematological malignancy, savvy factors that lead to CICI in hematological malignancies warrant attention.Patients and methodsThis is a cross-sectional discipline that was conducted at the Clinical Hematology Section in Ain Shams University Hospital during the period from March 2017 to September 2017. We studied the prevalence of cognitive deterioration among treated patients with chemotherapy for hematological malignancy, and we described its correlation to demographic data and risk agent. Test of cognitive function has been done by using Montreal Cognitive Assessment (MoCA).ResultsOut of 150 patients with different hematological malignancies who finished their chemotherapy at least 6 month ago, we found that 93 patient roles (62%) are cognitively impaired. The average score of Montreal test for all patient role was 23.913 ± 3.997. CICI is more among patient who received parenteral chemotherapies and closely related to premedication comorbidities, and all patients with myelodysplastic syndrome (MDS) were cognitively impaired. Also, there was a positive correlation between patient age and cognitive handicap as mean age of patients with abnormal cognitive function was 51.151 ± 9.933 (p value < 0.001) while period of hospital admission was showing significant correlation with impaired abstraction function (p value 0.003), and number of chemotherapy cycles showed significant correlation with naming and orientation cognitive impairment (p value 0.029 and 0.022, respectively). We found that female patients had significant shortcoming in naming ingredient more than male (p value 0.009). The type of chemotherapy regimen received did not significantly affected the overall cognitive impairment, but patients who had received Velcade-based chemotherapy had significantly lower executive and abstract function (p value 0.026). Patient roles which did not achieve remission at follow-up have markedly significant lower scores of most of the cognitive social function.Conclusion and recommendationCICI is a major problem in patient role with hematological malignance post-chemotherapy that can affect their quality of life, so fixture follow-up of the cognitive functions in those patients for early interference with proper management of risk factor is recommended.

Chemobrain: A Pilot Study Exploring the Severity and Onset of Chemotherapy-Related Cognitive Impairment.

Chemotherapy-related cognitive impairment refers to a cluster of symptoms commonly referred to as "chemobrain". To date, nursing literature on the progression of and tools used to evaluate chemobrain is limited. The purpose of this pilot study was to explore the onset of chemobrain in patients who recently began chemotherapy treatment, as well as those who have been receiving chemotherapy for an extended period of time. This prospective, nonrandomized, observational pilot feasibility study used the General Practitioner Assessment of Cognition and the Trail Making Test Parts A and B to examine chemotherapy-related cognitive impairment symptoms in patients undergoing chemotherapy treatment. Paired t tests showed a significant difference in scores on the Trail Making Test Part A from baseline to eight months (p < 0.05) and in scores on the Trail Making Test Part B from four to eight months (p < 0.05). The mixed results suggest that the Trail Making Test Parts A and B may not be effective for testing chemotherapy-related cognitive impairment in patients.

White Matter and Volumetric Changes in Children After Undergoing Chemotherapy

Purpose: Following chemotherapy, many patients report impairments in working memory (WM), concentration, and attention; this phenomenon has been termed “chemo brain”. The purpose of this study was to explore the correlation of neuroanatomical changes with behavioral tests in patients who previously underwent chemotherapy. Materials and Methods Five children previously treated with chemotherapy, on average 6 years prior (12.8±3.7yo) and fifteen age matched controls (17.4±4.84yo) were recruited. Subjects underwent a structural, …

The Lived Experience of Chemo Brain in Early Stage Breast Cancer in Women 50 and Under

The Lived Experience of Chemo Brain in Early Stage Breast Cancer in Women 50 and Under