The impact of mindfulness on cancer-related cognitive impairment in breast cancer survivors with cognitive complaints.

BACKGROUND: Interventions that target cancer-related cognitive impairment (CRCI) to improve the quality of life of cancer survivors are needed. In this study, the potential of a mindfulness-based intervention to reduce CRCI in breast cancer survivors, compared with physical training and a wait list control group, was investigated. METHODS: Breast cancer survivors with cognitive complaints (N = 117) were randomly allocated to a mindfulness (n = 43), physical training (n = 36), or wait list control condition (n = 38). Participants completed neuropsychological tests and questionnaires before the intervention, immediately after, and 3 months after intervention. The primary outcome measure was the change in cognitive complaints over time. Secondary outcomes were objective cognitive impairment and psychological well-being. All outcomes were compared between groups over time using linear mixed models, including participants with missing values. RESULTS: Of the 117 included participants, 96 completed the three assessments. Participants in the three groups reported decreased cognitive complaints after intervention, without group differences. There were no between-group differences in objective cognitive impairment after intervention compared with baseline. Compared with the wait list control group, participants reported increased mindfulness skills and reduced emotional distress after mindfulness and reduced emotional distress and fatigue after physical training. CONCLUSION: Contrary to the hypothesis, all groups reported an improvement in cognitive complaints over time. It is suggested that priming and acknowledgment of CRCI might alter the experience of cognitive impairment. Additionally, both mindfulness-based intervention and physical training can improve psychological well-being of breast cancer survivors with cognitive complaints.

A systematic review on the use of quantitative imaging to detect cancer therapy adverse effects in normal-appearing brain tissue.

Cancer therapy for both central nervous system (CNS) and non-CNS tumors has been previously associated with transient and long-term cognitive deterioration, commonly referred to as 'chemo fog'. This therapy-related damage to otherwise normal-appearing brain tissue is reported using post-mortem neuropathological analysis. Although the literature on monitoring therapy effects on structural magnetic resonance imaging (MRI) is well established, such macroscopic structural changes appear relatively late and irreversible. Early quantitative MRI biomarkers of therapy-induced damage would potentially permit taking these treatment side effects into account, paving the way towards a more personalized treatment planning.This systematic review (PROSPERO number 224196) provides an overview of quantitative tomographic imaging methods, potentially identifying the adverse side effects of cancer therapy in normal-appearing brain tissue. Seventy studies were obtained from the MEDLINE and Web of Science databases. Studies reporting changes in normal-appearing brain tissue using MRI, PET, or SPECT quantitative biomarkers, related to radio-, chemo-, immuno-, or hormone therapy for any kind of solid, cystic, or liquid tumor were included. The main findings of the reviewed studies were summarized, providing also the risk of bias of each study assessed using a modified QUADAS-2 tool. For each imaging method, this review provides the methodological background, and the benefits and shortcomings of each method from the imaging perspective. Finally, a set of recommendations is proposed to support future research.

Effects of a mindfulness-based intervention on cancer-related cognitive impairment: Results of a randomized controlled functional magnetic resonance imaging pilot study.

BACKGROUND: Many breast cancer survivors suffer from cognitive complaints after cancer treatment, affecting their quality of life. The objective of this pilot study was to investigate the effect of a blended-care mindfulness-based intervention (MBI) on chemotherapy-related cognitive impairment and functional brain changes. Furthermore, correlations between changes in cognitive functioning and self-reported behavioral factors were investigated. METHODS: Breast cancer survivors (n = 33) who reported cognitive impairment were randomly allocated to a mindfulness condition (n = 18) or a waitlist control condition (n = 15). Patients completed questionnaires on cognitive impairment, emotional distress, and fatigue; neuropsychological tests; and resting-state functional magnetic resonance imaging before the start of MBI (time 1 [T1]), immediately after the completion of an 8-week MBI program (T2), and 3 months postintervention (T3). Resting-state functional connectivity was estimated in the default mode network, the dorsal and salience attention networks, and the frontoparietal network. Mixed model repeated-measures analysis was performed to test the intervention effect. RESULTS: Patients in the mindfulness condition exhibited significantly higher connectivity between the dorsal and salience attention networks after the mindfulness intervention compared with those in the control condition. MBI participants also had reduced subjective cognitive impairment, emotional distress, and fatigue. No intervention effect was observed on neurocognitive tests. CONCLUSIONS: MBI may induce functional brain changes in networks related to attention and may have a positive effect on subjective measures of cognitive impairment in breast cancer survivors. Therefore, MBI could be a suitable intervention to improve quality of life in this population and deserves further study in this context.

Age-dependent brain volume and neuropsychological changes after chemotherapy in breast cancer patients.

This study investigated volumetric brain changes and cognitive performance in premenopausal and postmenopausal patients treated for early-stage breast cancer. Participants underwent elaborate neurocognitive assessments (neuropsychological testing, cognitive failure questionnaire, and high-resolution T1-weighted structural MRI) before and after chemotherapy. Volumetric brain changes were estimated, using longitudinal deformation-based morphometry, and correlated with cognitive changes. In total, 180 women participated in this study, of whom 72 patients with breast cancer had received adjuvant chemotherapy (C+), 49 patients did not receive chemotherapy (C-), and 59 healthy controls (HC). The population was categorized into two age groups: A young group who were premenopausal and younger than 52 years at baseline (n = 55C+/32C-/41HC), and an older group who were postmenopausal and older than 60 years (n = 17C+/17C-/18HC). Cognitive impairment occurred after chemotherapy in both young and older patients, although older patients showed more decline in processing speed (Trail making test b). White matter volume expansion was observed after chemotherapy, only significantly present in the younger subgroup of patients. In patients not treated with chemotherapy, diffuse gray and white matter volume reduction was observed. Less white matter expansion concurred with more cognitive decline (r > .349, p < .05). In conclusion, we found age-dependent cognitive decline and white matter volume changes in patients with breast cancer after chemotherapy, which could possibly be linked to neuroinflammatory processes. White matter expansion after chemotherapy, more pronounced in premenopausal patients, correlated with less cognitive decline. This suggests such expansion to be age-dependent, possibly caused by a protective response in the younger brain to chemotherapy-induced neurotoxicity.

Genetic Modulation of Neurocognitive Development in Cancer Patients throughout the Lifespan: a Systematic Review.

The rise in cancer survival rates has raised concerns about the long-term adverse effects of cancer treatment, including neurocognitive impairment. Neurocognitive deficits such as attention and processing speed are frequently observed and can have a profound, lifelong impact in daily life of cancer patients. Interestingly, large interpatient variability exists in cognitive outcomes. Emerging evidence indicates that such differences may be related to genetic variation. The aim of our review was to systematically summarize the current literature on the modulatory effects of germline genetic polymorphisms on cancer treatment-induced cognitive changes and the potential age-dependent impact in cancer survivors. The PubMed/Medline database was screened using an extensive search string focusing on four components: "cancer", "cancer treatment", "neurocognitive outcome" and "germline genetic variation". Seventeen studies meeting predefined eligibility criteria were analyzed, including sixteen candidate gene studies and one genome-wide association study. 38 polymorphisms in 15 genes across proposed pathophysiological pathways, including (1) neural plasticity and repair, (2) neuroinflammation and defenses against oxidative stress, (3) neurotransmission, and (4) folate metabolism pathway, were reported to be significantly associated with treatment-related neurocognitive dysfunction or neuroimaging abnormalities. Still, some study results remained discordant, partly due to the methodological heterogeneity (i.e. in test assessments, age, cancer-type populations). Future large-scale, (epi-)genome studies integrating neurocognitive assessments and advanced neuroimaging techniques, are recommended in order to investigate neurotoxicity throughout the lifespan. Hence, adverse neurodevelopmental problems during childhood and neurodegenerative processes later in life could be minimized based on genetic risk classifications.

Long-term leukoencephalopathy and neurocognitive functioning in childhood sarcoma patients treated with high-dose intravenous chemotherapy.

PURPOSE: Knowledge is limited regarding the prevalence and persistence of chemotherapy-induced leukoencephalopathy in childhood sarcoma patients. This study explored the presence, clinical relevance, and potential risk factors of leukoencephalopathy in childhood bone and soft tissue sarcoma survivors, treated with intravenous chemotherapy. METHODS: We acquired cross-sectional neurocognitive data in adult survivors (n = 34) (median age at diagnosis [AaD] = 13.32 years, age range = 16-35 years) and healthy age-matched controls (n = 34). Additionally, magnetic resonance imaging included T2-weighted FLAIR (leukoencephalopathy Fazekas rating), multiexponential T2 relaxation (MET2), and multishell diffusion MRI to estimate myelin integrity-related metrics and fluid movement restrictions. Finally, chemotherapy subgroups (methotrexate, alkylating agents, or combination), AaD, and Apoε and MTHFRC677T polymorphisms were explored as potential risk factors for leukoencephalopathy. RESULTS: At the group level, quality of life, working memory, processing speed, and visual memory were significantly lower in patients compared to controls. Furthermore, long-term leukoencephalopathy was observed in 27.2% of the childhood sarcoma survivors, which was related to attentional processing speed. Lesions were related to diffusion-derived, but not to myelin-sensitive metrics. A significant interaction effect between AaD and chemotherapy group demonstrated more lesions in case of high-dose methotrexate (HD-MTX) (F = 3.434, P = .047). However, patients treated with alkylating agents (without HD-MTX) also showed lesions in younger patients. Genetic predictors were nonsignificant. CONCLUSION AND IMPLICATION: This study suggests long-term leukoencephalopathy with possibly underlying changes in vasculature, inflammation, or axonal injury, but not necessarily long-term demyelination. Such lesions could affect processing speed, and as such long-term daily life functioning of these patients.

Advanced MR diffusion imaging and chemotherapy-related changes in cerebral white matter microstructure of survivors of childhood bone and soft tissue sarcoma?

With the increase of survival rates of pediatric cancer patients, the number of children facing potential cognitive sequelae has grown. Previous adult studies suggest that white matter (WM) microstructural changes may contribute to cognitive impairment. This study aims to investigate WM microstructure in childhood bone and soft tissue sarcoma. Differences in (micro-)structure can be investigated using diffusion MRI (dMRI). The typically used diffusion tensor model (DTI) assumes Gaussian diffusion, and lacks information about fiber populations. In this study, we compare WM structure of childhood bone and soft tissue sarcoma survivors (n = 34) and matched controls (n = 34), combining typical and advanced voxel-based models (DTI and NODDI model, respectively), as well as recently developed fixel-based models (for estimations of intra-voxel differences, apparent fiber density [AFD] and fiber cross-section [FC]). Parameters with significant findings were compared between treatments, and correlated with subscales of the WAIS-IV intelligence test, age at diagnosis, age at assessment and time since diagnosis. We encountered extensive regions showing lower fractional anisotropy, overlapping with both significant NODDI parameters and fixel-based parameters. In contrast to these diffuse differences, the fixel-based measure of AFD was reduced in the cingulum and corpus callosum only. Furthermore, AFD of the corpus callosum was significantly predicted by chemotherapy treatment and correlated positively with time since diagnosis, visual puzzles and similarities task scores. This study suggests altered WM structure of childhood bone and soft tissue sarcoma survivors. We conclude global chemotherapy-related changes, with particular vulnerability of centrally located WM bundles. Finally, such differences could potentially recover after treatment.

Intellectual development of childhood ALL patients: a multicenter longitudinal study.

BACKGROUND: In childhood acute lymphoblastic leukemia (ALL), radiotherapy for CNS prophylaxis is not used in frontline therapy anymore. Standard treatment for ALL nowadays consists of polychemotherapy. Therefore, assessment of potential chemotherapy-induced cognitive side effects becomes important. Although neurotoxicity was demonstrated in cross-sectional studies, longitudinal studies remain scarce. PROCEDURE: We evaluated intellectual development of 94 pediatric ALL patients between 1990 and 1997, diagnosed before the age of 12 years, treated according to the European Organisation for Research and Treatment of Cancer Children's Leukemia Group 58881 protocol. Three assessments of the Wechsler Intelligence Scale for Children Revised were performed since diagnosis, according to age. Using repeated measures regression analysis, we investigated the effect of gender (low versus increased) risk group, parents' education, age at diagnosis, intelligence quotient (IQ) subscale (verbal (VIQ) versus performance (PIQ) intelligence), and test session. RESULTS: PIQ scores were lower than VIQ at baseline (-5.3 points on average, p = 0.0032), yet PIQ increased more strongly (PIQ: +3.9 points per test session; VIQ: +0.8, p = 0.0079), so this baseline difference disappeared (p = 0.0079). There were no clear effects of gender (girls: +0.6 points; p = 0.78) or risk group (low risk: +1.5 points; p = 0.49), but IQ scores were higher when one parent had followed higher education (+9.5 points, p < 0.0001). Finally, diagnosis at younger age predicted lower IQ scores (-1.3 points per year, p = 0.0009). CONCLUSION: Given that IQ scores did not decline, our findings demonstrate a stable pattern. However, the lower PIQ scores at baseline may indicate that performance functioning is vulnerable to acute neurotoxicity. Also, lower scores for younger patients highlight the stronger impact of the disease and/or treatment at younger age.Copyright © 2016 John Wiley & Sons, Ltd.

Hippocampal avoidance prophylactic cranial irradiation (HA-PCI) for small cell lung cancer reduces hippocampal atrophy compared to conventional PCI.

BACKGROUND: Reducing radiation dose to the hippocampus with hippocampal avoidance prophylactic cranial irradiation (HA-PCI) is proposed to prevent cognitive decline. It has, however, not been investigated whether hippocampal atrophy is actually mitigated by this approach. Here, we determined whether HA-PCI reduces hippocampal atrophy. Additionally, we evaluated neurotoxicity of (HA-)PCI to other brain regions. Finally, we evaluated associations of hippocampal atrophy and brain neurotoxicity with memory decline. METHODS: High-quality research MRI scans were acquired in the multicenter, randomized phase 3 trial NCT01780675. Hippocampal atrophy was evaluated for 4 months (57 HA-PCI patients and 46 PCI patients) and 12 months (28 HA-PCI patients and 27 PCI patients) after (HA-)PCI. We additionally studied multimodal indices of brain injury. Memory was assessed with the Hopkins Verbal Learning Test-Revised (HVLT-R). RESULTS: HA-PCI reduced hippocampal atrophy at 4 months (1.8% for HA-PCI and 3.0% for PCI) and at 12 months (3.0% for HA-PCI and 5.8% for PCI). Both HA-PCI and PCI were associated with considerable reductions in gray matter and normal-appearing white matter, increases in white matter hyperintensities, and brain aging. There were no significant associations between hippocampal atrophy and memory. CONCLUSIONS: HA-PCI reduces hippocampal atrophy at 4 and 12 months compared to regular PCI. Both types of radiotherapy are associated with considerable brain injury. We did not find evidence for excessive brain injury after HA-PCI relative to PCI. Hippocampal atrophy was not associated with memory decline in this population as measured with HVLT-R. The usefulness of HA-PCI is still subject to debate.

A Systematic Review on the Potential Acceleration of Neurocognitive Aging in Older Cancer Survivors.

As survival rates increase, more emphasis has gone to possible cognitive sequelae in older cancer patients, which could be explained by accelerated brain aging. In this review, we provide a complete overview of studies investigating neuroimaging, neurocognitive, and neurodegenerative disorders in older cancer survivors (>65 years), based on three databases (Pubmed, Web of Science and Medline). Ninety-six studies were included. Evidence was found for functional and structural brain changes (frontal regions, basal ganglia, gray and white matter), compared to healthy controls. Cognitive decline was mainly found in memory functioning. Anti-hormonal treatments were repeatedly associated with cognitive decline (tamoxifen) and sometimes with an increased risk of Alzheimer's disease (androgen deprivation therapy). Chemotherapy was inconsistently associated with later development of cognitive changes or dementia. Radiotherapy was not associated with cognition in patients with non-central nervous system cancer but can play a role in patients with central nervous system cancer, while neurosurgery seemed to improve their cognition in the short-term. Individual risk factors included cancer subtypes (e.g., brain cancer, hormone-related cancers), treatment (e.g., anti-hormonal therapy, chemotherapy, cranial radiation), genetic predisposition (e.g., APOE, COMT, BDNF), age, comorbidities (e.g., frailty, cognitive reserve), and psychological (e.g., depression, (post-traumatic) distress, sleep, fatigue) and social factors (e.g., loneliness, limited caregiver support, low SES). More research on accelerated aging is required to guide intervention studies.

The Impact of Mindfulness on Functional Brain Connectivity and Peripheral Inflammation in Breast Cancer Survivors with Cognitive Complaints.

BACKGROUND: Cancer-related cognitive impairment (CRCI) has been linked to functional brain changes and inflammatory processes. Hence, interventions targeting these underlying mechanisms are needed. In this study, we investigated the effects of a mindfulness-based intervention on brain function and inflammatory profiles in breast cancer survivors with CRCI. METHODS: Female breast cancer survivors reporting cognitive complaints (n = 117) were randomly assigned to a mindfulness-based intervention (n = 43), physical training (n = 36), or waitlist control condition (n = 38). Region-of-interest (ROI) and graph theory analyses of resting state functional MRI data were performed to study longitudinal group differences in functional connectivity and organization in the default mode, dorsal attention, salience, and frontoparietal network. Additionally, bead-based immunoassays were used to investigate the differences in inflammatory profiles on serum samples. Measures were collected before, immediately after and three months post-intervention. RESULTS: No ROI-to-ROI functional connectivity changes were identified. Compared to no intervention, graph analysis showed a larger decrease in clustering coefficient after mindfulness and physical training. Additionally, a larger increase in global efficiency after physical training was identified. Furthermore, the physical training group showed a larger decrease in an inflammatory profile compared to no intervention (IL-12p70, IFN-γ, IL-1ß, and IL-8). CONCLUSION: Both mindfulness and physical training induced changes in the functional organization of networks related to attention, emotion processing, and executive functioning. While both interventions reduced functional segregation, only physical training increased functional integration of the neural network. In conclusion, physical training had the most pronounced effects on functional network organization and biomarkers of inflammation, two mechanisms that might be involved in CRCI.

Changes in leukoencephalopathy and serum neurofilament after (neo)adjuvant chemotherapy for breast cancer.

BACKGROUND: Previous case studies have provided evidence for chemotherapy-induced leukoencephalopathy in patients with breast cancer. However, prospective research is lacking. Hence, we investigated leukoencephalopathy before and after chemotherapy and its association with a serum neuroaxonal damage marker. METHODS: This prospective cohort study included 40 patients receiving chemotherapy for breast cancer, and two age- and education-matched control groups, recruited between 2018 and 2021 (31-64 years of age). The latter control groups consisted of 39 chemotherapy-naïve patients and 40 healthy women. Fluid-attenuated inversion-recovery magnetic resonance imaging was used for lesion volumetry (total, juxtacortical, periventricular, infratentorial, and deep white matter) and blood serum to measure neurofilament light chain (NfL) levels. Acquisition took place pre-chemotherapy and three months and one-year post-chemotherapy, or at corresponding intervals. Within/between group differences were compared using robust mixed-effects modeling, and associations between total lesion volume and serum-NfL with linear regression. RESULTS: Stronger increases in deep white matter lesion volumes were observed shortly post-chemotherapy, compared with healthy women (ßstandardized=0.09, pFDR<0.001). Increases in total lesion volume could mainly be attributed to enlargement of existing lesions (mean±SD, 0.12±0.16 mL), rather than development of new lesions (0.02±0.02 mL). A stronger increase in serum-NfL concentration was observed shortly post-chemotherapy compared with both control groups (ß>0.70, p<0.004), neither of which showed any changes over time, whereas a decrease was observed compared with healthy women one-year post-chemotherapy (ß=-0.54, p = 0.002). Serum-NfL concentrations were associated with lesion volume one-year post-chemotherapy (or at matched timepoint; ß=0.36, p = 0.010), whereas baseline or short-term post-therapy levels or changes were not. CONCLUSION: These results underscore the possibility of chemotherapy-induced leukoencephalopathy months post-treatment, as well as the added value of serum-NfL as a prognostic marker for peripheral/central neurotoxicity. TRANSLATIONAL RELEVANCE: Previous case studies have provided evidence of chemotherapy-induced leukoencephalopathy in patients with breast cancer. However, prospective studies to estimate longitudinal changes are currently missing. In this study, we used longitudinal fluid-attenuated inversion-recovery magnetic resonance imaging to assess white matter lesion volumes in patients treated for non-metastatic breast cancer and healthy women. Our findings demonstrate that chemotherapy-treated patients exhibit stronger increases in lesion volumes compared with healthy women, specifically in deep white matter, at three months post-chemotherapy. Increases could mainly be attributed to enlargement of existing lesions, rather than development of new lesions. Last, serum concentrations of neurofilament light chain, a neuroaxonal damage marker, increased shortly after chemotherapy and long-term post-chemotherapy levels were associated with lesion volumes. These findings highlight the potential of this non-invasive serum marker as a prognostic marker for peripheral and/or central neurotoxicity. Implementation in clinical practice could aid in therapeutic decisions, assessing disease activity, or monitoring treatment response.

The impact of mindfulness on working memory-related brain activation in breast cancer survivors with cognitive complaints.

PURPOSE: Cancer-related cognitive impairment (CRCI) has been associated with altered brain activation after chemotherapy in areas related to working memory. Hence, improving working memory capacity and associated brain activation might aid in the recovery of CRCI. In this study, we investigated the potential of a mindfulness-based intervention (MBI) to impact working memory-related brain activation. METHODS: Female breast cancer survivors reporting cognitive complaints (N=117) were randomized into a mindfulness (n=43; MBI), physical training (n=36; PT), or waitlist control condition (n=38; WL). Participants completed MRI scans before the intervention, immediately after, and three months post-intervention. Task-based functional MRI was used to measure differences between groups over time in working memory-related brain activation while performing a visual-verbal n-back task. RESULTS: Data of 83 participants (32/26/25 MBI/PT/WL) was included. Compared to the waitlist group, MBI participants showed reduced task-related activation in the right middle frontal and angular gyrus and increased activation in the right dorsal posterior cingulate cortex over time. Compared to the physical training group, MBI participants showed reduced brain activation in the bilateral superior parietal lobule and right dorsal anterior cingulate cortex over time. No differences between physical training and no intervention were identified. CONCLUSION: This study showed that an 8-week mindfulness-based intervention can significantly alter brain activation across brain regions involved in working memory, attentional control, and emotion processing during performance of a working memory task. This might aid in the recovery of CRCI. IMPLICATIONS FOR CANCER SURVIVORS: Mindfulness might alter brain activation patterns while performing a working memory task, which might ultimately aid in restoring higher order cognitive functions.

Correction: Schroyen et al. Neuroinflammation and Its Association with Cognition, Neuronal Markers and Peripheral Inflammation after Chemotherapy for Breast Cancer. Cancers 2021, 13, 4198.

In the original publication [...].

Brain gray matter reduction and premature brain aging after breast cancer chemotherapy: a longitudinal multicenter data pooling analysis.

Brain gray matter (GM) reductions have been reported after breast cancer chemotherapy, typically in small and/or cross-sectional cohorts, most commonly using voxel-based morphometry (VBM). There has been little examination of approaches such as deformation-based morphometry (DBM), machine-learning-based brain aging metrics, or the relationship of clinical and demographic risk factors to GM reduction. This international data pooling study begins to address these questions. Participants included breast cancer patients treated with (CT+, n = 183) and without (CT-, n = 155) chemotherapy and noncancer controls (NC, n = 145), scanned pre- and post-chemotherapy or comparable intervals. VBM and DBM examined GM volume. Estimated brain aging was compared to chronological aging. Correlation analyses examined associations between VBM, DBM, and brain age, and between neuroimaging outcomes, baseline age, and time since chemotherapy completion. CT+ showed longitudinal GM volume reductions, primarily in frontal regions, with a broader spatial extent on DBM than VBM. CT- showed smaller clusters of GM reduction using both methods. Predicted brain aging was significantly greater in CT+ than NC, and older baseline age correlated with greater brain aging. Time since chemotherapy negatively correlated with brain aging and annual GM loss. This large-scale data pooling analysis confirmed findings of frontal lobe GM reduction after breast cancer chemotherapy. Milder changes were evident in patients not receiving chemotherapy. CT+ also demonstrated premature brain aging relative to NC, particularly at older age, but showed evidence for at least partial GM recovery over time. When validated in future studies, such knowledge could assist in weighing the risks and benefits of treatment strategies.

Neuroinflammation as potential precursor of leukoencephalopathy in early-stage breast cancer patients: A cross-sectional PET-MRI study.

BACKGROUND: Although chemotherapy-induced leukoencephalopathy has been described in case and cohort studies, literature remains inconclusive about its prevalence and mechanisms. Therefore, we investigated the presence of leukoencephalopathy after multiagent chemotherapy in women treated for breast cancer and potential underlying neuroinflammatory processes. METHODS: In this exploratory study, 15 chemotherapy-treated and 15 age-matched chemotherapy-naïve patients with early-stage breast cancer, as well as 15 healthy controls underwent simultaneous PET-MR neuroimaging, including T1-weighted MPRAGE, T2-weighted FLAIR and dynamic PET with the 18-kDA translocator protein (TSPO) radioligand [18F]DPA-714. Total and regional (juxtacortical, periventricular, deep white matter and infratentorial) lesion burden were compared between the groups with one-way ANOVA. With paired t-tests, [18F]DPA-714 volume of distribution [VT, including partial volume correction (PVC)] in lesioned and normal appearing white matter (NAWM) were compared within subjects, to investigate inflammation. Finally, two general linear models were used to examine the predictive values of neurofilament light-chain (NfL) serum levels on (1) total lesion burden or (2) PVC [18F]DPA-714 VT of lesions showing elevated inflammation. RESULTS: No significant differences were found in total or localized lesion burden. However, significantly higher (20-45%) TSPO uptake was observed in juxtacortical lesions (p ≤ 0.008, t ≥ 3.90) compared to NAWM in both cancer groups, but only persisted for chemotherapy-treated patients after PVC (p = 0.005, t = 4.30). NfL serum levels were not associated with total lesion volume or tracer uptake in juxtacortical lesions. CONCLUSION: This multimodal neuroimaging study suggests that neuroinflammatory processes could be involved in the development of juxtacortical, but not periventricular or deep white matter, leukoencephalopathy shortly after chemotherapy for early-stage breast cancer.

Blood and neuroimaging biomarkers of cognitive sequelae in breast cancer patients throughout chemotherapy: A systematic review.

Breast cancer treatment can induce alterations in blood- and neuroimaging-based markers. However, an overview of the predictive value of these markers for cognition is lacking for breast cancer survivors. This systematic review summarized studies of the last decade, using the PubMed database, evaluating blood markers, and the association between blood- or structural neuroimaging markers and cognition across the chemotherapy trajectory for primary breast cancer, following PRISMA guidelines. Forty-four studies were included. Differences were observed in all blood marker categories, from on-therapy until years post-chemotherapy. Associations were found between cognitive functioning and (1) blood markers (mainly inflammation-related) during, shortly-, or years post-chemotherapy and (2) white and gray matter metrics in frontal, temporal and parietal brain regions months up until years post-chemotherapy. Preliminary evidence exists for epigenetic and metabolic changes being associated with cognition, only after chemotherapy. This review demonstrated time-dependent associations between specific blood-based and structural neuroimaging markers with cognitive impairment in patients with breast cancer. Future studies are encouraged to include both neuroimaging- and blood markers (e.g. of neuronal integrity, epigenetics and metabolism) to predict long-term cognitive effects of chemotherapy.

Cerebral glucose changes after chemotherapy and their relation to long-term cognitive complaints and fatigue.

Purpose: To investigate the short-term cerebral metabolic effects of intravenous chemotherapy and their association with long-term fatigue/cognitive complaints. Experimental design: Using [18F]-FDG-PET/CT whole-body scans, we retrospectively quantified relative cerebral glucose metabolism before and after neoadjuvant chemotherapy in a cohort of patients treated for non-metastatic breast cancer (2009-2019). Self-report of cognitive complaints and fatigue were prospectively assessed 7 ± 3 years after therapy. Metabolic changes were estimated with i) robust mixed-effects modelling in regions-of-interest (frontal, parietal, temporal, occipital, and insular cortex) and ii) general-linear modelling of whole-brain voxel-wise outcomes. iii) The association between metabolic changes and self-reported outcomes was evaluated using linear regression-analysis. Results: Of the 667 screened patients, 263 underwent PET/CT before and after chemotherapy and 183 (48 ± 9 years) met the inclusion criteria. After chemotherapy, decreased frontal and increased parietal and insular metabolism were observed (|ß|>0.273, pFDR <0.008). Separately, additional increased occipital metabolism after epiribucin+ cyclophosphamide (EC) and temporal metabolism after EC+ fluorouracil chemotherapy were observed (ß>0.244, pFDR ≤0.048). Voxel-based analysis (pcluster-FWE <0.001) showed decreased metabolism in the paracingulate gyrus (-3.2 ± 3.9%) and putamen (3.1 ± 4.1%) and increased metabolism in the lateral cortex (L=2.9 ± 3.1%) and pericentral gyri (3.0 ± 4.4%). Except for the central sulcus, the same regions showed changes in EC, but not in FEC patients. Of the 97 self-reported responders, 23% and 27% experienced extreme fatigue and long-term cognitive complaints, respectively, which were not associated with metabolic changes. Conclusion: Both hyper- and hypometabolism were observed after chemotherapy for breast cancer. Combined with earlier findings, this study could support inflammatory mechanisms resulting in relative hypermetabolism, mainly in the parietal/occipital cortices. As early metabolic changes did not precede long-term complaints, further research is necessary to identify vulnerable patients.

Cancer-related cognitive impairment in non-CNS cancer patients: Targeted review and future action plans in Europe.

Cancer-related cognitive impairment (CRCI) has increasingly been identified over the last two decades in non-CNS system cancer patients. Across Europe, researchers have contributed to this effort by developing preclinical models, exploring underlying mechanisms and assessing cognitive and quality of life changes. The ultimate goal is to develop interventions to treat patients experiencing CRCI. To do so, new challenges need to be addressed requiring the implementation of multidisciplinary research groups. In this consensus paper, we summarize the state of the art in the field of CRCI combined with the future challenges and action plans in Europe. These challenges include data sharing/pooling, standardization of assessments as well as assessing additional biomarkers and neuroimaging investigations, notably through translational studies. We conclude this position paper with specific actions for Europe based on shared scientific expert opinion and stakeholders involved in the Innovative Partnership for Action Against Cancer, with a particular focus on cognitive intervention programs.

Chemotherapy-induced structural changes in cerebral white matter and its correlation with impaired cognitive functioning in breast cancer patients.

A subgroup of patients with breast cancer suffers from mild cognitive impairment after chemotherapy. To uncover the neural substrate of these mental complaints, we examined cerebral white matter (WM) integrity after chemotherapy using magnetic resonance diffusion tensor imaging (DTI) in combination with detailed cognitive assessment. Postchemotherapy breast cancer patients (n = 17) and matched healthy controls (n = 18) were recruited for DTI and neuropsychological testing, including the self-report cognitive failure questionnaire (CFQ). Differences in DTI WM integrity parameters [fractional anisotropy (FA) and mean diffusivity (MD)] between patients and healthy controls were assessed using a voxel-based two-sample-t-test. In comparison with healthy controls, the patient group demonstrated decreased FA in frontal and temporal WM tracts and increased MD in frontal WM. These differences were also confirmed when comparing this patient group with an additional control group of nonchemotherapy-treated breast cancer patients (n = 10). To address the heterogeneity observed in cognitive function after chemotherapy, we performed a voxel-based correlation analysis between FA values and individual neuropsychological test scores. Significant correlations of FA with neuropsychological tests covering the domain of attention and processing/psychomotor speed were found in temporal and parietal WM tracts. Furthermore, CFQ scores correlated negatively in frontal and parietal WM. These studies show that chemotherapy seems to affect WM integrity and that parameters derived from DTI have the required sensitivity to quantify neural changes related to chemotherapy-induced mild cognitive impairment.