Chemobrain Research Articles

Methotrexate Chemotherapy Induces Persistent Tri-glial Dysregulation that Underlies Chemotherapy-Related Cognitive Impairment

Chemotherapy results in a frequent yet poorly understood syndrome of long-term neurological deficits. Neural precursor cell dysfunction and white matterdysfunction are thought to contribute to thisdebilitating syndrome. Here, we demonstrate persistent depletion of oligodendrocyte lineage cells in humans who received chemotherapy. Developing amouse model of methotrexate chemotherapy-induced neurological dysfunction, we find a similar depletion of white matter OPCs, increased but incomplete OPC differentiation, and a persistent deficit in myelination. OPCs from chemotherapy-naive mice similarly exhibit increased differentiation when transplanted into the microenvironment of previously methotrexate-exposed brains, indicating an underlying microenvironmental perturbation. Methotrexate results in persistent activation of microglia and subsequent astrocyte activation that isdependent on inflammatory microglia. Microglialdepletion normalizes oligodendroglial lineage dynamics, myelin microstructure, and cognitive behavior after methotrexate chemotherapy. These findings indicate that methotrexate chemotherapy exposure is associated with persistent tri-glial dysregulation and identify inflammatory microglia as atherapeutic target to abrogate chemotherapy-related cognitive impairment. VIDEO ABSTRACT.

How does chemo brain work? One cancer drug might interfere with brain signaling

How does chemo brain work? One cancer drug might interfere with brain signaling

Understanding the Collateral Damage of Treating Acute Myeloid Leukemia: An Estimate of Patient-Reported Side Effect Rates from a National Survey

Introduction: Symptom management is considered a top priority of cancer care. Monitoring patient-reported outcomes (PROs) such as side effects of treatment has been shown to improve quality of life and even prolong survival among cancer patients. For regulators, PROs collected from patients and the caregivers who speak for patients when they are too ill or unable to speak for themselves informs patient-focused drug development (PFDD). PFDD is a key-component of the 21st Century Cures Act that aligns FDA, industry, advocacy and academic partners to accelerate medical product development for those who need it most. We sought to understand the prevalence of side effects experienced by people with acute myeloid leukemia (AML) and to assess differences in the report of side effects from patients across the disease trajectory, including those who were deceased or too ill to directly self-report.Methods: We assessed patient reported prevalence of severe short- and long-term side effects from AML treatments as a part of a national survey. Caregiver reports were included so as to capture the experiences of patients who had either passed away from AML or who were too ill to participate. Participants rated their experience with short-term side effects (nausea, infection, mouth sores, diarrhea, hair loss) and long-term side effects (organ dysfunction, neuropathy, fatigue, chemo brain) as 'none,' 'mild,' 'moderate,' or 'severe.' Prevalence of severe side effects was assessed using descriptive statistics, and differences in likelihood of reporting severe side effects were assessed using logistic regression.Results: A total of 1182 eligible participants completed the survey, including 901 patients and 281 caregivers. Participants were an average of 55 years old (SD=13.0), and 12% were non-white minorities. Patient participants had been diagnosed with AML for 7.7 years (SD=4.7), while patients reported on by caregiver participants had been diagnosed for 5.7 years (SD=4.1). Almost all participants received chemotherapy (98%), and one-fifth received radiation (21%). Hair loss was the most common severe short-term side effect among caregivers (68%) as well as patients (79%, p=0.01). Conversely, patients were less likely than caregivers to report a severe infection (29% vs 36%, p<0.001). Patients and caregivers reported similar rates of other short-term side effects, including mouth sores (33 % vs 34%, p=0.22), diarrhea (29% vs 32%, p=0.07), nausea (27% vs 24%, p=0.26), and rash (20% for both; p=0.80). Patients were consistently less likely to report severe, long-term side effects as compared to caregivers, including fatigue (20% vs 34%, p<0.001), neuropathy (8% vs 15%, p=0.02) and organ dysfunction (5% vs 22%, p<0.001). Patients and caregivers reported similar rates of severe ‘chemo brain’ (11% vs 15%, p=0.43).Conclusions: AML patients of diverse disease stages experience side effects as well as long-lasting collateral damage from treatments. PRO measures can collect important prevalence data for these events. As compared to their healthier patient counterparts, caregivers reporting on deceased or ill patients demonstrated similar rates of severe short-term side effects, but higher rates of long-term, collateral damages from their treatment. Despite the difficulty in objective quantification, that over 10% of the sample reported severe ‘chemo brain’ validates the disease community's continued interest in better understanding this experience through PFDD. [Display omitted] DisclosuresBridges:The Leukemia & Lymphoma Society: Research Funding.

Chemotherapy-related cognitive impairment: mechanisms, clinical features and research perspectives.

The term chemotherapy-related cognitive impairment (CRCI), or cognitive dysfunction, or chemo fog, or chemo brain, is referred to a decline in a variety of neuropsychological tasks after chemotherapy, or following other anticancer treatments such as radiation therapy or surgery, in patients with non-central nervous system cancers. Furthermore, several pieces of evidence suggest that clinical manifestations of cognitive impairment may occur in cancer patients, prior to chemotherapy or in those not treated with cancer therapies. In these circumstances, it should be more appropriate to use the term cancer-related cognitive dysfunction. Because there is no consensus about its definition and diagnostic criteria, no specific test for CRCI diagnose exists. Whatever the cause, this manifestation of central nervous system toxicity is of increasing concern as the survival rates for cancer have improved steadily and, in turn, cognitive dysfunction can negatively impact the patients and cancer survivors' quality of life. The aim of this work is to offer an overview of the topic and recommendations for future research.

125 - The triangle of death of neurons, oxidative damage, mitochondrial dysfunction, and loss of choline-containing biomolecules, in brains of mice treated with doxorubicin: advanced insights into mechanisms of “chemobrain”

Depending on the published study, from 30 % to 70 % of cancer survivors who had undergone chemotherapy reported cognitive dysfunction, usually manifested as memory impairment, difficulty with reasoning, and problems multi-tasking, consistent with deficits of higher executive functioning. This chemotherapy induced cognitive impairment (CICI), often called “chemobrain” by patients, is a major contributor to decreased quality of life for a large percentage of the more than the current 15 million cancer survivors in the USA. More than 50 % of FDA-approved anti-cancer drugs are associated with reactive oxygen species (ROS) as part of their mechanisms of action. Doxorubicin (Dox) is a prototypical ROS generating chemotherapeutic agent used to treat solid tumors and lymphomas as part of multi-drug chemotherapeutic regimens. Dox produces the reactive superoxide radical anion (O2•–) in vivo through quinone to semi-quinone redox cycling. Neither Dox nor its major metabolite crosses the blood brain barrier. We previously reported that intraperitoneal (i.p.) Dox-administration to mice leads to plasma protein damage and elevation of tumor necrosis factor-alpha (TNF-α) in plasma and brain. We further reported that TNF-α elevation in brain leads to further central nervous system toxicity, including oxidative stress, mitochondrial dysfunction, neuronal death, and cognitive impairment. In the present study, we tested the hypothesis that TNF-α in brain was critical to these deleterious effects that contribute to CICI. We demonstrate that oxidative stress is ameliorated and mitochondrial function assessed by the Seahorse-determined oxygen consumption rate (OCR) is preserved in brain of Dox-treated TNF-α knockout (TNFKO) mice. Further, we show in TNFKO mouse brain protection against Dox-related decreased Cho/Cr ratio determined by magnetic resonance spectroscopy (MRS) and protection against loss of phospholipase D (PLD) activity. Coupled with findings from our previous studies, these current results provide important insights into the role of TNF-α in CICI.

Adaptogens in chemobrain (Part I): Plant extracts attenuate cancer chemotherapy-induced cognitive impairment – Transcriptome-wide microarray profiles of neuroglia cells

BackgroundCancer chemotherapy-induced cognitive impairments are presumably associated with undesirable effects of chemotherapy on physiological functions of brain cells. Adaptogens are natural compounds or plant extracts increasing an organism's adaptability and survival in stress. They exhibited neuroprotective effects and increased cognitive functions in clinical studies in human beings. HypothesisWe hypothesized that selected adaptogenic plant extracts attenuate or prevent cancer chemotherapy-induced cognitive impairments. AimWe assessed the effects of selected adaptogenic herbal extracts on FEC (fixed combination 5-fluorouracil, epirubicin and cyclophosphamide) induced changes in transcriptome-wide RNA microarray profiles of neuroglia cells. The aim of the study was to predict potential effects of andrographolide, Andrographis herb, Eleutherococcus root genuine extracts, their fixed combination (AE) and the combination of Rhodiola roots, Schisandra berries and Eleutherococcus roots (RSE) on cellular and physiological, mostly cognitive functions. MethodsGene expression profiling was performed by transcriptome-wide mRNA microarray in the human T98G neuroglia cells after treatment with adaptogens. Interactive pathways downstream analysis was performed with data sets of significantly up- or down-regulated genes and predicted effects on cellular functions and diseases were identified by Ingenuity IPA database software. ResultsFEC deregulated 67 genes involved in decrease of neuronal development, 37 genes involved in development of the sensory system, 12 genes in extension of axons, and 3 genes in migration of neurons. Co-incubation with Andrographis paniculata (AP) suppressed FEC-induced deregulation of a large number of genes involved in predicted activation of neuronal death and inhibition of neurogenesis, and 16 genes related to inhibition of several functions in the nervous system. Co-incubation with AE suppressed FEC-induced deregulation of a number of genes involved in predicted inhibition of axon extension, migration of T98G neuroglia cells, conduction of nerves and other genes related to regulations of some other functions in the nervous system. ConclusionApplication of cytostatic drugs in combination with apoptogenic plant extracts induced significant changes in transcriptome-wide mRNA microarray profiles of neuroglial cells. These changes indicate on potential beneficial effects on neuronal functions associated with mild cognitive impairments in cancer chemotherapy.

Pharmacological inhibition of HDAC6 reverses cognitive impairment and tau pathology as a result of cisplatin treatment

Chemotherapy-induced cognitive impairment (CICI) is a commonly reported neurotoxic side effect of chemotherapy, occurring in up to 75% cancer patients. CICI manifests as decrements in working memory, executive functioning, attention, and processing speed, and greatly interferes with patients’ daily performance and quality of life. Currently no treatment for CICI has been approved by the US Food and Drug Administration. We show here that treatment with a brain-penetrating histone deacetylase 6 (HDAC6) inhibitor for two weeks was sufficient to fully reverse cisplatin-induced cognitive impairments in male mice, as demonstrated in the Y-maze test of spontaneous alternation, the novel object/place recognition test, and the puzzle box test. Normalization of cognitive impairment was associated with reversal of cisplatin-induced synaptosomal mitochondrial deficits and restoration of synaptic integrity. Mechanistically, cisplatin induced deacetylation of the microtubule protein α-tubulin and hyperphosphorylation of the microtubule-associated protein tau. These cisplatin-induced changes were reversed by HDAC6 inhibition. Our data suggest that inhibition of HDAC6 restores microtubule stability and reverses tau phosphorylation, leading to normalization of synaptosomal mitochondrial function and synaptic integrity and thereby to reversal of CICI. Remarkably, our results indicate that short-term daily treatment with the HDAC6 inhibitor was sufficient to achieve prolonged reversal of established behavioral, structural and functional deficits induced by cisplatin. Because the beneficial effects of HDAC6 inhibitors as add-ons to cancer treatment have been demonstrated in clinical trials, selective targeting of HDAC6 with brain-penetrating inhibitors appears a promising therapeutic approach for reversing chemotherapy-induced neurotoxicity while enhancing tumor control.

Chemotherapy-Induced Cognitive Impairment Is Associated with Cytokine Dysregulation and Disruptions in Neuroplasticity.

Chemotherapy-induced cognitive impairment, often referred to as "chemobrain," is a common side effect. In this study, mice received three intraperitoneal injections of a combination of docetaxel, adriamycin, and cyclophosphamide (DAC) at 2-day intervals. A water maze test was used to examine cognitive performance, and manganese-enhanced magnetic resonance imaging (MEMRI) was used to examine hippocampal neuronal activity. The whole brain, prefrontal cortex, hippocampus, and blood samples were then collected for cytokine measurement. The DAC-treated mice displayed a significantly shorter duration spent in and fewer entries into the target quadrant of the water maze than the control mice and a pronounced decrease in MEMRI signal intensity in the hippocampal subregions. In a separate experiment using in vivo transcranial two-photon imaging, DAC markedly eliminated dendritic spines without changing the rate of spine formation, leading to a striking loss of spines in the medial prefrontal cortex. DAC treatment resulted in significant elevations in the levels of the proinflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) and in significant decreases in the levels of the anti-inflammatory cytokines IL-4 and IL-10 in most of the sera and brain tissues examined. The IL-6 and TNF-α levels of several sera and brain tissues showed strong inverse correlations with the duration and number of entries in the target quadrant of the water maze and with the hippocampal MEMRI signal intensity, but also showed striking positive correlations with spine elimination and loss. These results indicate that chemobrain is associated with cytokine dysregulation and disrupted neuroplasticity of the brain.

Doxorubicin-induced elevated oxidative stress and neurochemical alterations in brain and cognitive decline: protection by MESNA and insights into mechanisms of chemotherapy-induced cognitive impairment ("chemobrain").

Chemotherapy-induced cognitive impairment (CICI) is now widely recognized as a real and too common complication of cancer chemotherapy experienced by an ever-growing number of cancer survivors. Previously, we reported that doxorubicin (Dox), a prototypical reactive oxygen species (ROS)-producing anti-cancer drug, results in oxidation of plasma proteins, including apolipoprotein A-I (ApoA-I) leading to tumor necrosis factor-alpha (TNF-α)-mediated oxidative stress in plasma and brain. We also reported that co-administration of the antioxidant drug, 2-mercaptoethane sulfonate sodium (MESNA), prevents Dox-induced protein oxidation and subsequent TNF-α elevation in plasma. In this study, we measured oxidative stress in both brain and plasma of Dox-treated mice both with and without MESNA. MESNA ameliorated Dox-induced oxidative protein damage in plasma, confirming our prior studies, and in a new finding led to decreased oxidative stress in brain. This study also provides further functional and biochemical evidence of the mechanisms of CICI. Using novel object recognition (NOR), we demonstrated the Dox administration resulted in memory deficits, an effect that was rescued by MESNA. Using hydrogen magnetic resonance imaging spectroscopy (H1-MRS) techniques, we demonstrated that Dox administration led to a dramatic decrease in choline-containing compounds assessed by (Cho)/creatine ratios in the hippocampus in mice. To better elucidate a potential mechanism for this MRS observation, we tested the activities of the phospholipase enzymes known to act on phosphatidylcholine (PtdCho), a key component of phospholipid membranes and a source of choline for the neurotransmitter, acetylcholine (ACh). The activities of both phosphatidylcholine-specific phospholipase C (PC-PLC) and phospholipase D were severely diminished following Dox administration. The activity of PC-PLC was preserved when MESNA was co-administered with Dox; however, PLD activity was not protected. This study is the first to demonstrate the protective effects of MESNA on Dox-related protein oxidation, cognitive decline, phosphocholine (PCho) levels, and PC-PLC activity in brain and suggests novel potential therapeutic targets and strategies to mitigate CICI.

From the Bottom-Up: Chemotherapy and Gut-Brain Axis Dysregulation.

The central nervous system and gastrointestinal tract form the primary targets of chemotherapy-induced toxicities. Symptoms associated with damage to these regions have been clinically termed chemotherapy-induced cognitive impairment and mucositis. Whilst extensive literature outlines the complex etiology of each pathology, to date neither chemotherapy-induced side-effect has considered the potential impact of one on the pathogenesis of the other disorder. This is surprising considering the close bidirectional relationship shared between each organ; the gut-brain axis. There are complex multiple pathways linking the gut to the brain and vice versa in both normal physiological function and disease. For instance, psychological and social factors influence motility and digestive function, symptom perception, and behaviors associated with illness and pathological outcomes. On the other hand, visceral pain affects central nociception pathways, mood and behavior. Recent interest highlights the influence of functional gut disorders, such as inflammatory bowel diseases and irritable bowel syndrome in the development of central comorbidities. Gut-brain axis dysfunction and microbiota dysbiosis have served as key portals in understanding the potential mechanisms associated with these functional gut disorders and their effects on cognition. In this review we will present the role gut-brain axis dysregulation plays in the chemotherapy setting, highlighting peripheral-to-central immune signaling mechanisms and their contribution to neuroimmunological changes associated with chemotherapy exposure. Here, we hypothesize that dysregulation of the gut-brain axis plays a major role in the intestinal, psychological and neurological complications following chemotherapy. We pay particular attention to evidence surrounding microbiota dysbiosis, the role of intestinal permeability, damage to nerves of the enteric and peripheral nervous systems and vagal and humoral mediated changes.

Electrochemical Measurement of Dopamine Release and Uptake in Zebrafish Following Treatment with Carboplatin.

Post-chemotherapy cognitive impairment, also known as 'chemobrain,' is a neurological condition in which cognitive function is impaired as a result of cancer chemotherapy treatment. In this work, we used fast-scan cyclic voltammetry (FSCV) to measure electrically evoked dopamine release and uptake in whole brain preparations from zebrafish that have been treated with carboplatin, an agent associated with chemobrain. We administered carboplatin by addition to the fish's tank water or their food. One week of treatment with 100 μM carboplatin in the water was needed to significantly impair dopamine release (∼40 % of control); however, only one day of treatment through the zebrafish's food was needed to cause a similar impairment. Atomic absorption spectroscopy measurements suggested that administration through food resulted in higher initial levels of carboplatin compared to water administration, but water administration resulted in an increase over time. Uptake, determined by modeling stimulated release plots, was unaffected. These results are consistent with our previous findings of diminished neurotransmitter release in rats and support a role for zebrafish in chemobrain-related studies.

Identifying cytokine predictors of cognitive functioning in breast cancer survivors up to 10 years post chemotherapy using machine learning

IntroductionThe purpose of this study is to explore 13 cytokine predictors of chemotherapy-related cognitive impairment (CRCI) in breast cancer survivors (BCS) 6 months to 10 years after chemotherapy completion using a multivariate, non-parametric approach. MethodsCross sectional data collection included completion of a survey, cognitive testing, and non-fasting blood from 66 participants. Data were analyzed using random forest regression to identify the most significant predictors for each of the cognitive test scores. ResultsA different cytokine profile predicted each cognitive test. Adjusted R2 for each model ranged from 0.71–0.77 (p's < 9.50–10). The relationships between all the cytokine predictors and cognitive test scores were non-linear. ConclusionsOur findings are unique to the field of CRCI and suggest non-linear cytokine specificity to neural networks underlying cognitive functions assessed in this study.

Physical exercise prevents cognitive impairment by enhancing hippocampal neuroplasticity and mitochondrial function in doxorubicin-induced chemobrain

Although chemotherapy increases the survival rate of patients with various cancers, such treatment can induce acute or long-term cognitive dysfunction a phenomenon known as post-chemotherapy cognitive impairment (PCCI) or “chemobrain.” Exercise is known to positively affect brain function. Thus, the present study aimed to determine whether symptoms of chemobrain and disruptions in the neuroplasticity and functioning of hippocampal mitochondria can be prevented or relieved by exercise. Wistar rats were separated into the following groups: control, control plus exercise, chemobrain, and chemobrain plus exercise. For chemobrain induction, 2 mg/kg of doxorubicin (DOX) a widely utilized chemotherapeutic agent among patients with breast cancer was dissolved in saline and directly injected to the abdomen once every 4 weeks. The exercise groups were subjected to low-intensity treadmill, 6 days per week for 4 weeks. The Morris water maze and step-down avoidance tests were conducted to evaluate cognitive function, while neuroplasticity and mitochondrial function were assessed in the hippocampus and dentate gyrus. Decreased cognitive function were observed in the chemobrain group, along with decreases in levels of neurogenesis, brain derived neurotrophic factor (BDNF), tropomyosin-related kinase B (TrkB), Ca2+ retention in hippocampus. Rats of the chemobrain group also exhibited an increase in apoptosis, H2O2 emission and permeability transition pore by hippocampal mitochondria. However, exercise attenuated impairments in cognitive function, neuroplasticity, and mitochondrial function induced by DOX treatment. Therefore, the findings of the present study indicate that low-intensity exercise may assist in preventing cognitive dysfunction during or after chemotherapy in patients with various cancers, including breast cancer.

Resveratrol, a natural polyphenol, prevents chemotherapy-induced cognitive impairment: Involvement of cytokine modulation and neuroprotection

Chemotherapy-induced cognitive impairment, also known as “chemobrain,” is a common side effect. The purpose of this study was to examine whether resveratrol, a natural polyphenol that has nootropic effects, could prevent chemobrain and its underlying mechanisms. Mice received three injections of docetaxel, adriamycin, and cyclophosphamide (DAC) in combination, a common chemotherapy regimen, at two-day intervals within one week. Resveratrol (50 and 100 mg/kg per day) was orally administered for three weeks, beginning one week before the DAC treatment. Water maze test and manganese-enhanced magnetic resonance imaging were used to evaluate animals' cognitive performance and brain neuronal activity, respectively. Blood and brain tissues were collected for measurement of cytokines, cytokine regulators, and biomarkers for neuroplasticity. DAC treatment produced a striking cognitive impairment. Cotreatment with 100 mg/kg resveratrol ameliorated DAC-induced cognitive impairment and decreases in prefrontal and hippocampal neuronal activity. Mice co-treated with both doses of resveratrol displayed significantly lower levels of the proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), but markedly higher levels of the anti-inflammatory cytokines IL-4 and IL-10 in several sera and brain tissues than those co-treated with vehicle. Resveratrol modulated the cytokine-regulating pathway peroxisome proliferator activated receptor (PPAR)-γ/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and protected against DAC-induced decreases in the expression of the neuroplasticity biomarkers, brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB), amino acid neurotransmitter receptors, and calmodulin-dependent protein kinase II (CaMKII). These results demonstrate the efficacy of resveratrol in preventing chemobrain and its association with cytokine modulation and neuroprotection.

Growth of Triple Negative and Progesterone Positive Breast Cancer Causes Oxidative Stress and Down-Regulates Neuroprotective Transcription Factor NPAS4 and NPAS4-Regulated Genes in Hippocampal Tissues of TumorGraft Mice-an Aging Connection.

While the refinement of existing and the development of new chemotherapeutic regimens has significantly improved cancer treatment outcomes and patient survival, chemotherapy still causes many persistent side effects. Central nervous system (CNS) toxicity is of particular concern, as cancer patients experience significant deficits in memory, learning, cognition, and decision-making. These chemotherapy-induced cognitive changes are termed chemo brain, and manifest in more than half of cancer survivors. Moreover, recent studies have emerged suggesting that neurocognitive deficits manifest prior to cancer diagnosis and treatment, and thus may be associated with tumor presence, a phenomenon recently termed “tumor brain.” To dissect the molecular mechanisms of tumor brain, we used TumorGraftTM models, wherein part of a patient's tumor is grafted into immune-deficient mice. Here, we analyzed molecular changes in the hippocampal tissues of mice carrying triple negative (TNBC) or progesterone receptor positive (PR+BC) xenografts. TNBC growth led to increased oxidative damage, as detected by elevated levels of 4-hydroxy-2-nonenal, a product of lipid peroxidation. Furthermore, the growth of TNBC and PR+BC tumors altered global gene expression in the murine hippocampus and affected multiple pathways implicated in PI3K-Akt and MAPK signaling, as well as other pathways crucial for the proper functioning of hippocampal neurons. TNBC and PR+BC tumor growth also led to a significant decrease in the levels of neuronal transcription factor NPAS4, a regulator that governs the expression of brain-derived neurotrophic factor (BDNF), and several other key brain neurotrophic factors and pro-survival molecules. The decreased expression of ERK1/2, NPAS4, and BDNF are also seen in neurodegenerative conditions and aging, and may constitute an important tumor brain mechanism.

A brief intervention for chemobrain: Results from a pilot study.

171 Background: Up to 75 percent of breast cancer survivors (BCS) who were treated with chemotherapy report difficulty with cognition, including word finding problems and an inability to attend or multitask. The phenomenon of chemotherapy-related cognitive impairment is often referred to as “Chemobrain.” Chemobrain negatively affects one’s family and social and professional lives. In addition, anxiety and depression – commonly found in breast cancer survivors –negatively affect one’s cognition. An intervention for chemobrain needs to also address these psychological disorders in order to increase the quality of life of BCS. Methods: BCS who completed chemotherapy in the past 5 years and complained of subsequent cognitive decline were recruited for an intervention that included mindfulness and cognitive rehabilitation. Mindfulness has been shown to help with attention and to decrease depression and anxiety. The intervention was given in a class setting and met once/week for 1.5 hours for 6 weeks. Participants completed a brief neuropsychological battery pre- and post-intervention. Results: Immediately post-intervention, all participants (n = 11, mean age = 53.7 years, 100% female) reported increased cognitive functioning as measured by FACT-Cognitive Function, with a mean increase of 27.7 points (p &lt; 0.01, d= 1.82). Ninety-one percent of participants reported decreased depression as measured by PHQ-9, with a mean decrease of 4.7 points (p = 0.02, d= 0.82). These improvements were sustained 3 months post-intervention in cognitive functioning (p &lt; 0.01, d= 2.04) and depression (p &lt; 0.01, d = 1.39). Improved performance was also found in verbal fluency (p = 0.02, d= 0.87) and executive functioning as measured by Trail Making Test B (p = 0.02, d= 0.82). No improvement was detected in verbal learning or processing speed. Conclusions: Breast cancer survivors with chemobrain can recover cognitive functioning and decrease levels of depression relatively quickly with an intervention that combines mindfulness and cognitive rehabilitation. This recovery can be sustained for at least 3 months post-intervention. Additional research is needed to investigate how long recovery can be maintained and if the same intervention can help other cancer survivors.

Distinct and heterogeneous trajectories of self‐perceived cognitive impairment among Asian breast cancer survivors

Currently, there are no studies that have established the self-perceived cognitive trajectories experienced by breast cancer patients (BCPs) post-chemotherapy. Therefore, we characterized the long-term trajectory of self-perceived cognitive function among Asian early-stage BCPs using the minimal clinically important difference of a subjective measure of cognitive function. Early-stage BCPs who received chemotherapy were recruited and assessed at 4 time points: Before chemotherapy initiation (T1), 6weeks post-chemotherapy initiation (T2), 12weeks post-chemotherapy initiation (T3), and 15-months post-chemotherapy initiation (T4). All assessments were performed approximately within 2weeks post-chemotherapy. Subjective and objective cognitive function were assessed using Functional Assessment of Cancer Therapy-Cognitive (version 3) and Headminder™. A total of 166 BCPs were recruited, of whom 131 completed assessment at all time points. Using the minimal clinically important difference of Functional Assessment of Cancer Therapy-Cognitive, 5 distinct cognitive trajectories were established. Of the 131 patients, 70 (53.4%) did not report any clinically significant cognitive impairment. Twenty-one (16.0%) patients reported acute cognitive changes during chemotherapy (T2 and/or T3) but not at T4. Forty patients (30.5%) reported clinically significant cognitive impairment at T4, of whom 18 did not report any cognitive impairment at earlier time points. Fifteen (11.5%) patients reported persistent cognitive impairment throughout all time points, while 7 (5.3%) patients reported intermittent cognitive impairment at T2 and T4 but not at T3. This is the first study to establish the existence of heterogeneous cognitive trajectories based on clinically significant thresholds of self-perceived cognitive impairment. The findings have important implications on the window for screening and management of post-chemotherapy cognitive impairment.

PAN-811 prevents chemotherapy-induced cognitive impairment and preserves neurogenesis in the hippocampus of adult rats.

Chemotherapy-induced cognitive impairment (CICI) occurs in a substantial proportion of treated cancer patients, with no drug currently available for its therapy. This study investigated whether PAN-811, a ribonucleotide reductase inhibitor, can reduce cognitive impairment and related suppression of neurogenesis following chemotherapy in an animal model. Young adult rats in Chemo and Chemo+PAN-811 groups received 3 intraperitoneal (i.p.) injections of methotrexate (MTX) and 5-fluorouracil (5-FU), and those in Saline and Saline+PAN-811 groups received equal volumes of physiological saline at 10-day intervals. PAN-811 in saline was delivered through i.p. injection, 10 min following each saline (Saline+PAN-811 group) or MTX/5-FU (Chemo+PAN-811 group) treatment, while equal volumes of saline were delivered to Saline and Chemo groups. Over Days 31–66, rats were administered tests of spatial memory, nonmatching-to-sample rule learning, and discrimination learning, which are sensitive to dysfunction in hippocampus, frontal lobe and striatum, respectively. On Day 97, neurogenesis was immnunohistochemically evaluated by counting doublecortin-positive (DCX+) cells in the dentate gyrus (DG). The results demonstrated that the Chemo group was impaired on the three cognitive tasks, but co-administration of PAN-811 significantly reduced all MTX/5-FU-induced cognitive impairments. In addition, MTX/5-FU reduced DCX+ cells to 67% of that in Saline control rats, an effect that was completely blocked by PAN-811 co-administration. Overall, we present the first evidence that PAN-811 protects cognitive functions and preserves neurogenesis from deleterious effects of MTX/5-FU. The current findings provide a basis for rapid clinical translation to determine the effect of PAN-811 on CICI in human.

Association of mitochondrial DNA content in peripheral blood with cancer-related fatigue and chemotherapy-related cognitive impairment in early-stage breast cancer patients: a prospective cohort study.

Cancer-related fatigue (CRF) and chemotherapy-related cognitive impairment (CRCI) are reported to be associated with mitochondrial dysfunction. Hence, mitochondrial DNA (mtDNA) content, a biomarker of mitochondrial dysfunction, is hypothesized to correlate with the onset of CRF and CRCI. This study aims to evaluate the association between peripheral blood mtDNA content reduction and severity of CRF and CRCI in patients receiving chemotherapy. This was a prospective cohort study. Early-stage breast cancer patients receiving anthracycline- or taxane-based chemotherapy were recruited. CRF was assessed using MFSI-SF, and CRCI was assessed using FACT-Cog and CANTAB at two timepoints: baseline (T1; prior to treatment) and 6weeks after initiation of treatment (T2). mtDNA content was measured at both timepoints using real-time quantitative polymerase chain reaction. Multiple logistic regression was utilized to evaluate the association between mtDNA reduction and worsening of CRF and CRCI, adjusting for age, anxiety, insomnia, plasma cytokines concentrations, and other clinically important covariates. A total of 108 patients (age 52.0±9.2years; 82.4% Chinese; 64.8% receiving anthracycline-based chemotherapy) were recruited. Proportions of patients with worsening of CRF increased from the lower to the upper quartiles of mtDNA reduction (22.2, 33.3, 55.6, and 63.0% in quartiles 1, 2, 3, and 4, respectively,p=0.001 for trend). Reduction of mtDNA content was significantly greater among those with worsening of CRF and CRCI compared to those without CRF [mean reduction (±SD): 36.5 (46.1) vs. 9.4 (34.5), p<0.001]. After adjusting for covariates, every 1-unit reduction of the mtDNA content was associated with a 4% increased risk for worsening of CRF (95% CI, 1-6%; p=0.009). This is the first study to show that the reduction of mtDNA content in peripheral blood is associated with the onset of CRF in patients receiving chemotherapy. Further validation studies are required to confirm the findings.

Neuroimmunological Manifestations of Chemotherapy Exposure: Implications for Mucositis, Glia and Cognition

Chemotherapy drugs reduce quality of life often causing acute and delayed central side-effects, termed chemotherapy-induced cognitive impairment (CICI). Another dose-limiting chemotherapy-induced side-effect is oral and intestinal mucositis which results in significant gastrointestinal (GIT) damage and intestinal inflammation. Recent interest has been paid to neurological complications arising in patients with gut disorders, yet little attention has been paid to the role GIT damage plays in CICI. Our current understanding of neuronal adaptations and behavioral consequences resulting from immune system dysregulation has paved the way for investigation into the neuroimmunological manifestations associated with chemotherapy. In a clinical setting cancer patients experience a cluster of symptoms, similar to that manifested in cytokine-induced sickness responses. Accordingly, it is suggested that peripheral inflammatory events, such as chemotherapy-induced mucositis, may indirectly cause glial dysregulation and potentiate cognitive changes in CICI. Perhaps it is time to examine the cancer experience in a multidisciplinary manner, in order to encapsulate the direct and indirect mechanisms underlying treatment-related side-effects. Specifically, understanding the neuroimmunological implications of chemotherapy-induced mucositis will provide further insight into the direct and indirect mechanisms underlying CICI pathogenesis.