Nasal administration of mitochondria reverses chemotherapy-induced cognitive deficits.

Up to seventy-five percent of patients treated for cancer suffer from cognitive deficits which can persist for months to decades, severely impairing quality of life. Although the number of cancer survivors is increasing tremendously, no efficacious interventions exist. Cisplatin, most commonly employed for solid tumors, leads to cognitive impairment including deficits in memory and executive functioning. We recently proposed deficient neuronal mitochondrial function as its underlying mechanism. We hypothesized nasal administration of mitochondria isolated from human mesenchymal stem cells to mice, can reverse cisplatin-induced cognitive deficits. Methods: Puzzle box, novel object place recognition and Y-maze tests were used to assess the cognitive function of mice. Immunofluorescence and high-resolution confocal microscopy were employed to trace the nasally delivered mitochondria and evaluate their effect on synaptic loss. Black Gold II immunostaining was used to determine myelin integrity. Transmission electron microscopy helped determine mitochondrial and membrane integrity of brain synaptosomes. RNA-sequencing was performed to analyse the hippocampal transcriptome. Results: Two nasal administrations of mitochondria isolated from human mesenchymal stem cells to mice, restored executive functioning, working and spatial memory. Confocal imaging revealed nasally delivered mitochondria rapidly arrived in the meninges where they were readily internalized by macrophages. The administered mitochondria also accessed the rostral migratory stream and various other brain regions including the hippocampus where they colocalized with GFAP+ cells. The restoration of cognitive function was associated with structural repair of myelin in the cingulate cortex and synaptic loss in the hippocampus. Nasal mitochondrial donation also reversed the underlying synaptosomal mitochondrial defects. Moreover, transcriptome analysis by RNA-sequencing showed reversal of cisplatin-induced changes in the expression of about seven hundred genes in the hippocampus. Pathway analysis identified Nrf2-mediated response as the top canonical pathway. Conclusion: Our results provide key evidence on the therapeutic potential of isolated mitochondria - restoring both brain structure and function, their capability to enter brain meninges and parenchyma upon nasal delivery and undergo rapid cellular internalization and alter the hippocampal transcriptome. Our data identify nasal administration of mitochondria as an effective strategy for reversing chemotherapy-induced cognitive deficits and restoring brain health, providing promise for the growing population of both adult and pediatric cancer survivors.

Potential for identification of memory problems in the cancer clinic to enable improved treatment experience and outcomes: Mixed methods case study research.

PURPOSE: To inform improvement in cancer treatment experience and outcomes for people with dementia or milder cognitive impairment. People with dementia, compared to those without, experience more side effects from cancer treatment and have poorer outcomes including poorer survival. METHODS: The research was a mixed methods exploratory case study. Each case was a cancer treatment in a person with memory loss, a common symptom of dementia. Observations were conducted in 30 clinic sessions at one cancer centre between September 2014 and February 2015. Thirty-three encounters between people with a memory problem and a staff member were observed and ten consultations recorded. Interviews were conducted with five staff members and six people receiving cancer treatment, five accompanied by their carer. Analysis, informed by hermeneutic phenomenology, enabled the treatment pathway to be mapped and modelled to reveal sites for intervention. FINDINGS: Five potential sites of intervention were identified in the treatment pathway. Five actions at the sites of intervention that may improve patient experience and outcomes include, raising awareness of common problems for people with cognitive impairment receiving cancer treatment, encouraging disclosure of memory problems, staff training to identify memory problems and to know what to do, offering tools and techniques to aid self-management of memory problems, and addressing carer support needs. CONCLUSION: Embedding biomedical treatment of cancer within a dementia-friendly psychosocial system may enable safe cancer treatment for a greater number of people with dementia or milder cognitive impairment.

A mindfulness-based intervention for breast cancer patients with cognitive impairment after chemotherapy: study protocol of a three-group randomized controlled trial.

BACKGROUND: Mindfulness has been applied to improve cancer care by enhancing psychological well-being. However, little is known about its impact on cognitive impairment experienced by cancer patients after chemotherapy. Mindfulness may be relevant in tackling cognitive impairment by decreasing emotional distress and fatigue, by decreasing inflammation, and by strengthening functional brain connectivity. The aim of the present study protocol is to evaluate the efficacy and mechanisms of a mindfulness-based intervention to reduce cognitive impairment in breast cancer patients after chemotherapy. METHODS/DESIGN: The present study is a three-arm, parallel-group, randomized controlled trial with assessments at baseline, 1 to 3 weeks after the intervention and at 3 months' follow-up. One hundred and twenty breast cancer patients who ended treatment a minimum of 6 months and a maximum of 5 years before, and who have cognitive complaints, will be enrolled. They will be randomized into one of the following three study arms: (1) a mindfulness-based intervention group (n = 40), (2) an active control condition based on physical training (n = 40), or (3) a treatment as usual (TAU) control group (n = 40). Both the mindfulness-based intervention and the active control condition consist of four group sessions (3 h for the mindfulness condition and 2 h for the physical training) spread over 8 weeks. The primary outcomes will be cognitive symptoms as measured by the Cognitive Failure Questionnaire and changes in functional brain connectivity in the attention network. Secondary outcomes will be (1) levels of emotional distress, fatigue, mindfulness, quality of life; (2) neurocognitive tests; (3) structural and functional brain changes using MR imaging and (4) measures of inflammation. DISCUSSION: The study will examine the impact of a mindfulness-based intervention on cognitive impairment in breast cancer patients. If the findings of this study confirm the effectiveness of a mindfulness-based program to reduce cognitive impairment, it will be possible to improve quality of life for ex-cancer patients. We will inform health care providers about the potential use of a mindfulness-based intervention as a non-pharmaceutical, low-threshold mental health intervention to improve cognitive impairment after cancer. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03736460. Retrospectively registered on 8 November 2018.

Post-chemotherapy cognitive impairment in hematological patients: current understanding of chemobrain in hematology.

Introduction: Cognitive impairment caused by chemotherapies, a condition known as chemobrain, is a possible side effect that affects alertness, learning, memory, and concentration.Areas covered: Chemobrain has been principally investigated as a possible side-effect among cancer patients. However, numerous drugs used to treat hematological malignancies can determine the appearance of chemobrain. In this review, we have examined some commonly used drugs for the treatment of hematological malignancies which are known to have a deleterious action on cognitive functions.Numerous mechanisms have been suggested, comprising the direct neurotoxicity of chemotherapeutic drugs, oxidative stress, genetic predisposition, cytokine-provoked damage, histone modifications, immune alteration, and the action of chemotherapeutic on trophic factors and structural proteins of brain cells.Expert commentary: Cognitive dysfunction provoked by the treatment of hematological diseases is an actual challenge in clinical practice. Actually, there are no totally efficient and innocuous treatments for this syndrome. It is important that further investigations specify the existence of predictors and gravity factors to pre- and post-therapy cognitive change and identify the influence of tumor treatments on the cognitive alterations in long-term, cancer survivors. Moreover, future studies are needed to analyze the interactions between genetic risk, amyloid accumulation, intrinsic brain networks, and chemotherapy.

Polydatin ameliorates chemotherapy-induced cognitive impairment (chemobrain) by inhibiting oxidative stress, inflammatory response, and apoptosis in rats.

Most breast cancer survivors receiving chemotherapy have severe cognitive impairment, often referred to as "chemobrain." Polydatin (PLD) is known to have many biological activities. Thus, this study aimed to determine whether symptoms of chemobrain can be prevented or relieved by PLD. The chemobrain models were established by intraperitoneal injection of doxorubicin (DOX, 2 mg/kg) in rats once a week for 4 weeks (DOX group and DOX+PLD group). In the PLD group and DOX+PLD group, PLD (50 mg/kg) was administered orally to rats every day. We found that PLD treatment significantly protected against DOX-induced learning and memory impairment, restored hippocampal histopathological architecture. Furthermore, PLD suppressed DOX-induced oxidative stress through up-regulating Nrf2, inhibited inflammatory response by activating the NF-κB pathway, and reduced hippocampal apoptosis. Therefore, the present study indicated that PLD offered neuroprotection against DOX-induced chemobrain. PLD may assist in preventing chemobrain after chemotherapy in patients with cancers.