Alterations in brain structure related to breast cancer and its treatment: Chemotherapy and other considerations

Cognitive effects of cancer and its treatment have been a topic of increasing investigation over the past ∼30 years. Recent studies have focused on better understanding the neural correlates of these effects, with an emphasis on post-chemotherapy effects in breast cancer patients. Structural MRI studies have utilized both automated and manual approaches to quantify gray and white matter characteristics (e.g., regional volume and density) in breast cancer patients treated with chemotherapy relative to patients who did not receive chemotherapy and/or healthy controls. While most work to date has been retrospective, a small number of baseline (pre-systemic therapy) and prospective longitudinal studies have been conducted. Data have consistently shown lower gray and white matter volume and density in patients treated with chemotherapy, particularly in frontal and temporal brain regions. Host factors and/or the cancer disease process and other therapies (e.g., antiestrogen treatment) also seem likely to contribute to the observed differences, though the relative contributions of these effects have not yet been investigated in detail. These structural abnormalities have been shown to relate to subjective and objective cognitive functioning, as well as to biological factors that may help to elucidate the underlying mechanism(s). This review examines the currently available published observations and discusses the major themes and promising directions for future studies

Imaging Brain Networks After Cancer and Chemotherapy: Advances Toward Etiology and Unanswered Questions

Comment on Neurotoxic Effects of Anthracycline- vs Nonanthracycline-Based Chemotherapy on Cognition in Breast Cancer Survivors. [JAMA Oncol. 2016

Neuroimaging, cancer, and cognition: state of the knowledge

OBJECTIVES: To review neuroimaging research concerning cancer- and cancer treatment-related changes in brain structure and function, clinical perspectives, and future directions. DATA SOURCES: Peer-reviewed literature. CONCLUSION: Cancer and chemotherapy are associated with cerebral structural and functional alterations in breast cancer patients that may persist for years; many of these changes are correlated with cognitive complaints or performance. In other cancers there is some evidence that metabolism is altered by cancer, but more research is needed. IMPLICATIONS FOR NURSING PRACTICE: Understanding the role of neuroimaging is important to identify the basis of cognitive changes associated with cancer and cancer treatment

In utero exposure to HIV and/or antiretroviral therapy: a systematic review of preclinical and clinical evidence of cognitive outcomes

Introducion With the increasing number of children exposed to HIV or antiretroviral therapy in utero, there are concerns that this population may have worse neurodevelopmental outcomes compared to those who are unexposed. The objective of this study was to systematically review the clinical and preclinical literature on the effects of in utero exposure to HIV and/or antiretroviral therapy (ART) on neurodevelopment. Methods We systematically searched OVID Medline, PsycINFO and Embase, as well as the Cochrane Collaborative Database, Google Scholar and bibliographies of pertinent articles. Titles, abstracts, and full texts were assessed independently by two reviewers. Data from included studies were extracted. Results are summarized qualitatively. Results The search yielded 3027 unique titles. Of the 255 critically reviewed full-text articles, 25 met inclusion criteria for the systematic review. Five articles studied human subjects and looked at brain structure and function. The remaining 20 articles were preclinical studies that mostly focused on behavioural assessments in animal models. The few clinical studies had mixed results. Some clinical studies found no difference in white matter while others noted higher fractional anisotropy and lower mean diffusivity in the brains of HIV-exposed uninfected children compared to HIV-unexposed uninfected children, correlating with abnormal neurobehavioral scores. Preclinical studies focused primarily on neurobehavioral changes resulting from monotherapy with either zidovudine or lamivudine. Various developmental and behavioural changes were noted in preclinical studies with ART exposure, including decreased grooming, decreased attention, memory deficits and fewer behaviours associated with appropriate social interaction. Conclusions While the existing literature suggests that there may be some neurobehavioral differences associated with HIV and ART exposure, limited data are available to substantially support these claims. More research is needed comparing neurobiological factors between HIV-exposed uninfected and HIV-unexposed uninfected children and using exposures consistent with current clinical care

Variants in the Mitochondrial Intermediate Peptidase (MIPEP) Gene are Associated with Gray Matter Density in the Alzheimer’s Disease Neuroimaging Initiative Cohort

poster abstractCancer and Alzheimer’s disease (AD) incidence is inversely correlated, but the genetic underpinnings of this relationship remain to be elucidated. Recent findings identified lower gray matter density in frontal regions of participants of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) with cancer history compared to those without such history, across diagnostic groups (Nudelman et al., 2014). Pathways proposed to impact cancer and AD, including metabolism and survival, may play an important role in the observed difference. To test this hypothesis, a genome-wide association study (GWAS) using mean frontal gray matter cluster values was performed for all Caucasian participants in this cohort with neuroimaging and genetic data (n=1405). Analysis covaried for age, sex, AD, and cancer history. Of the two genes with the most significant SNPs (p<10-5), WD repeat domain 5B (WDR5B) and mitochondrial intermediate peptidase (MIPEP), MIPEP was selected for further analysis given the hypothesis focus on metabolism. ANOVA analysis of MIPEP top SNP rs8181878 with frontal gray matter cluster values in SPSS indicated that while this SNP is significantly associated with gray matter density (p=2x10-6), no interaction was observed with cancer history or AD diagnosis. Furthermore, whole brain gray matter voxel-wise analysis of this SNP using Statistical Parametric Mapping 8 software showed that minor allele(s) of this SNP were significantly (PFWE<0.05) associated with higher gray matter density. These results suggest that the minor allele of MIPEP SNP rs8181878 may be protective against gray matter density loss, highlighting the importance of metabolic processes in aging and disease

Reliable change in neuropsychological assessment of breast cancer survivors

BACKGROUND: The purpose of this study was to enhance the current understanding and interpretation of longitudinal change on tests of neurocognitive function in individuals with cancer. Scores on standard neuropsychological instruments may be impacted by practice effects and other random forms of error. METHODS: The current study assessed the test-retest reliability of several tests and overarching cognitive domains comprising a neurocognitive battery typical of those used for research and clinical evaluation using relevant time frames. Practice effect-adjusted reliable change confidence intervals for test-retest difference scores based on a sample of patient-matched healthy controls are provided. RESULTS: By applying reliable change confidence intervals to scores from two samples of breast cancer patients at post-treatment follow-up assessment, meaningful levels of detectable change in cognitive functioning in breast cancer survivors were ascertained and indicate that standardized neuropsychological instruments may be subject to limitations in detection of subtle cognitive dysfunction over clinically relevant intervals, especially in patient samples with average to above average range baseline functioning. CONCLUSIONS: These results are discussed in relation to reported prevalence of cognitive change in breast cancer patients along with recommendations for study designs that enhance detection of treatment effects

Association of cancer history with Alzheimer's disease onset and structural brain changes

Epidemiological studies show a reciprocal inverse association between cancer and Alzheimer's disease (AD). The common mechanistic theory for this effect posits that cells have an innate tendency toward apoptotic or survival pathways, translating to increased risk for either neurodegeneration or cancer. However, it has been shown that cancer patients experience cognitive dysfunction pre- and post-treatment as well as alterations in cerebral gray matter density (GMD) on MRI. To further investigate these issues, we analyzed the association between cancer history (CA±) and age of AD onset, and the relationship between GMD and CA± status across diagnostic groups in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort study. Data was analyzed from 1609 participants with information on baseline cancer history and AD diagnosis, age of AD onset, and baseline MRI scans. Participants were CA+ (N = 503) and CA− (N = 1106) diagnosed with AD, mild cognitive impairment (MCI), significant memory concerns (SMC), and cognitively normal older adults. As in previous studies, CA+ was inversely associated with AD at baseline (P = 0.025); interestingly, this effect appears to be driven by non-melanoma skin cancer (NMSC), the largest cancer category in this study (P = 0.001). CA+ was also associated with later age of AD onset (P < 0.001), independent of apolipoprotein E (APOE) ε4 allele status, and individuals with two prior cancers had later mean age of AD onset than those with one or no prior cancer (P < 0.001), suggesting an additive effect. Voxel-based morphometric analysis of GMD showed CA+ had lower GMD in the right superior frontal gyrus compared to CA− across diagnostic groups (Pcrit < 0.001, uncorrected); this cluster of lower GMD appeared to be driven by history of invasive cancer types, rather than skin cancer. Thus, while cancer history is associated with a measurable delay in AD onset independent of APOE ε4, the underlying mechanism does not appear to be cancer-related preservation of GMD

Comparison of Season-Long Diffusivity Measures in a Cohort of Non-Concussed Contact and Non-Contact Athletes

Introduction: Concern surrounding short- and long-term consequences of participation in contact sports has become a significant public health topic. Previous literature utilizing diffusion tensor imaging in sports-related concussion has exhibited notable variety of analysis methods and analyzed regions of interest, and largely focuses on acute effects of concussion. The current study aimed to compare diffusivity metrics across a single season within athlete cohorts with no history of concussion. Methods: A prospective cohort of 75 contact and 79 non-contact division I athletes were compared across diffusion tensor imaging metrics (i.e. TRACULA); examinations were also performed assessing the relationship between neuroimaging metrics, head impact exposure metrics (in-helmet accelerometer), and neurocognitive variables. Assessment occurred at pre-and post-season time points. Results: Seasonal changes in fractional anisotropy and mean diffusivity values did not differ between athlete cohorts, nor did they differ within cohort groups, across pre- and post-season scans. Specific to contact athletes, positive associations were found between uncinate fasciculus mean diffusivity values and season linear acceleration (p =.018), season rotational acceleration (p =.017), and season hit severity (p =.021). Conclusions: Results suggest an influence of impact frequency, type, and severity on white matter integrity in select brain regions in contact athletes. Current findings expand our knowledge of anatomical changes over the course of a single season, and underscore the importance of considering methodology when interpreting findings in this population, as differing image analysis techniques may lead to different conclusions regarding significant effects