Epigenetic aging in older breast cancer survivors and noncancer controls: preliminary findings from the Thinking and Living with Cancer Study.

BACKGROUND: Cancer and its treatments may accelerate aging in survivors; however, research has not examined epigenetic markers of aging in longer term breast cancer survivors. This study examined whether older breast cancer survivors showed greater epigenetic aging than noncancer controls and whether epigenetic aging related to functional outcomes. METHODS: Nonmetastatic breast cancer survivors (n = 89) enrolled prior to systemic therapy and frequency-matched controls (n = 101) ages 62 to 84 years provided two blood samples to derive epigenetic aging measures (Horvath, Extrinsic Epigenetic Age [EEA], PhenoAge, GrimAge, Dunedin Pace of Aging) and completed cognitive (Functional Assessment of Cancer Therapy-Cognitive Function) and physical (Medical Outcomes Study Short Form-12) function assessments at approximately 24 to 36 and 60 months after enrollment. Mixed-effects models tested survivor-control differences in epigenetic aging, adjusting for age and comorbidities; models for functional outcomes also adjusted for racial group, site, and cognitive reserve. RESULTS: Survivors were 1.04 to 2.22 years biologically older than controls on Horvath, EEA, GrimAge, and DunedinPACE measures (p = .001-.04) at approximately 24 to 36 months after enrollment. Survivors exposed to chemotherapy were 1.97 to 2.71 years older (p = .001-.04), and among this group, an older EEA related to worse self-reported cognition (p = .047) relative to controls. An older epigenetic age related to worse physical function in all women (p < .001-.01). Survivors and controls showed similar epigenetic aging over time, but Black survivors showed accelerated aging over time relative to non-Hispanic White survivors. CONCLUSION: Older breast cancer survivors, particularly those exposed to chemotherapy, showed greater epigenetic aging than controls that may relate to worse outcomes. If replicated, measurement of biological aging could complement geriatric assessments to guide cancer care for older women.

Plasma levels of interleukin-6 mediate neurocognitive performance in older breast cancer survivors: The Thinking and Living With Cancer study.

BACKGROUND: Immune activation/inflammation markers (immune markers) were tested to explain differences in neurocognition among older breast cancer survivors versus noncancer controls. METHODS: Women >60 years old with primary breast cancer (stages 0-III) (n = 400) were assessed before systemic therapy with frequency-matched controls (n = 329) and followed annually to 60 months; blood was collected during annual assessments from 2016 to 2020. Neurocognition was measured by tests of attention, processing speed, and executive function (APE). Plasma levels of interleukin-6 (IL-6), IL-8, IL-10, tumor necrosis factor α (TNF-α), and interferon γ were determined using multiplex testing. Mixed linear models were used to compare results of immune marker levels by survivor/control group by time and by controlling for age, racial/ethnic group, cognitive reserve, and study site. Covariate-adjusted multilevel mediation analyses tested whether survivor/control group effects on cognition were explained by immune markers; secondary analyses examined the impact of additional covariates (e.g., comorbidity and obesity) on mediation effects. RESULTS: Participants were aged 60-90 years (mean, 67.7 years). Most survivors had stage I (60.9%) estrogen receptor-positive tumors (87.6%). Survivors had significantly higher IL-6 levels than controls before systemic therapy and at 12, 24, and 60 months (p ≤ .001-.014) but there were no differences for other markers. Survivors had lower adjusted APE scores than controls (p < .05). Levels of IL-6, IL-10, and TNF-α were related to APE, with IL-6 explaining part of the relationship between survivor/control group and APE (p = .01). The magnitude of this mediation effect decreased but remained significant (p = .047) after the consideration of additional covariates. CONCLUSIONS: Older breast cancer survivors had worse long-term neurocognitive performance than controls, and this relationship was explained in part by elevated IL-6.

An Examination of the Longitudinal Relationship Between Cognitive Function and Physical Activity Among Older Breast Cancer Survivors in the Thinking and Living With Cancer Study.

BACKGROUND: Older cancer survivors are at risk for cognitive decline. Physical activity can improve cognition, and better cognitive function may facilitate greater physical activity. PURPOSE: We examined the potential bidirectional relationship between cognitive function and physical activity in older breast cancer survivors and controls. METHODS: The sample included women with newly diagnosed, nonmetastatic breast cancer (n = 395) and women without cancer (n = 374) ages 60-98. Participants were recruited as part of a larger multisite study, assessed prior to systemic therapy, and followed yearly for 36 months. Attention, processing speed, and executive function was measured using six neuropsychological tests, self-reported cognitive function using the Perceived Cognitive Impairments subscale of the Functional Assessment of Cancer Therapy-Cognitive Function , and physical activity using the International Physical Activity Questionnaire-Short Form. Separate random intercepts cross-lagged panel models were used to examine the between- and within-person effects for survivors and controls, controlling for age, education, and study site. RESULTS: Survivors reported significantly less physical activity than controls at baseline (1,284.92 vs. 2,085.98 MET min/week, p < .05). When survivors reported higher activity, they simultaneously had better objective cognition at 12 months (ß = 0.24, p = .04) and reported better perceived cognition at 12 and 24 months (ß = 0.25, p = .03), but this relationship was not seen in controls. Cognition did not predict subsequent physical activity or vice versa in either group. CONCLUSIONS: Cognition and physical activity are cross-sectionally associated in survivors, but the expected prospective relationships were not found.

Physical activity may improve cognitive function for older cancer survivors; however, cognitive function may also affect the ability to organize oneself to be physically active. We examined this potential bidirectional relationship in a sample of 395 women with newly diagnosed, nonmetastatic breast cancer, and 374 noncancer controls. These women completed cognitive tests and surveys yearly for 36 months. Surveys included their subjective cognitive function and physical activity. We examined the relationships between cognitive function (both objective and subjective) and physical activity over time (baseline, 12, 24, and 36 months). We found that when cancer survivors reported higher physical activity, they had better objective cognitive function at 12 months, and they reported better subjective cognitive function at 12 and 24 months. However, physical activity did not predict cognitive function at later time points, and cognitive function did not predict physical activity at later time points. In controls, better subjective cognitive function was related to higher physical activity overall, but there were not relationships over time or at specific time points. This was an observational study; therefore, future research should consider the potential impact of cognitive function when older cancer survivors are attempting to increase their physical activity.

Multimodal MRI examination of structural and functional brain changes in older women with breast cancer in the first year of antiestrogen hormonal therapy.

PURPOSE: Cancer patients are concerned about treatment-related cognitive problems. We examined effects of antiestrogen hormonal therapy on brain imaging metrics in older women with breast cancer. METHODS: Women aged 60 + treated with hormonal therapy only and matched non-cancer controls (n = 29/group) completed MRI and objective and self-reported cognitive assessment at pre-treatment/enrollment and 12 months later. Gray matter was examined using voxel-based morphometry (VBM), FreeSurfer, and brain age calculations. Functional MRI (fMRI) assessed working memory-related activation. Analyses examined cross-sectional and longitudinal differences and tested associations between brain metrics, cognition, and days on hormonal therapy. RESULTS: The cancer group showed regional reductions over 12 months in frontal, temporal, and parietal gray matter on VBM, reduced FreeSurfer cortical thickness in prefrontal, parietal, and insular regions, and increased working memory-related fMRI activation in frontal, cingulate, and visual association cortex. Controls showed only reductions in fusiform gyrus on VBM and FreeSurfer temporal and parietal cortex thickness. Women with breast cancer showed higher estimated brain age and lower regional gray matter volume than controls at both time points. The cancer group showed a trend toward lower performance in attention, processing speed, and executive function at follow-up. There were no significant associations between brain imaging metrics and cognition or days on hormonal therapy. CONCLUSION: Older women with breast cancer showed brain changes in the first year of hormonal therapy. Increased brain activation during working memory processing may be a sign of functional compensation for treatment-related structural changes. This hypothesis should be tested in larger samples over longer time periods. GOV IDENTIFIER: NCT03451383.

Impact of taxane-based chemotherapy among older women with breast cancer on cognition and quality of life: a longitudinal pooled analysis.

PURPOSE: Older cancer patients are susceptible to long-term effects of chemotherapy, including cancer-related cognitive decline and impairments to quality of life. Taxane-based chemotherapies are associated with physical declines among older women and may negatively impact cognitive performance. We sought to examine whether changes in objective and subjective measures of cognitive performance and well-being differ among older breast cancer survivors as a function of taxane-based chemotherapy treatment regimens. METHODS: Individual-level data were pooled and harmonized from two large prospective studies of older (greater than 60 years) breast cancer survivors. Assessments were conducted prior to systemic therapy and up to 36 months after. Cognitive performance was assessed with objective (working memory, processing speed, and executive functions) and subjective tests and physical, emotional, and functional well-being were also assessed. RESULTS: One hundred and sixty-seven (M age = 67.3 years) women with 116 receiving chemotherapy with taxanes and 51 without taxanes contributed data. Declines in subjective cognition for both groups were significant between pre-treatment and 12-month follow-up. Significant improvements were seen on a measure of objective cognition (working memory) from 12 to 36 months. Measures of well-being improved from prior to systemic therapy to 12 months. Longitudinal changes across all measures did not vary as a function of receipt of taxane-based treatment. CONCLUSION: Older women who received treatment with taxanes did not have greater declines in cognitive performance or well-being than women receiving other chemotherapy regimens. Despite older cancer survivors being at greater risk for negative outcomes, treatment with taxane-based chemotherapies does not appear to exacerbate these health consequences.

Association of markers of tumor aggressivity and cognition in women with breast cancer before adjuvant treatment: The Thinking and Living with Cancer Study.

PURPOSE: Tumor features associated with aggressive cancers may affect cognition prior to systemic therapy. We evaluated associations of cognition prior to adjuvant therapy and tumor aggressivity in older breast cancer patients. METHODS: Women diagnosed with non-metastatic breast cancer (n = 705) ages 60-98 were enrolled from August 2010-March 2020. Cognition was measured post-surgery, pre-systemic therapy using self-reported (FACT-Cog Perceived Cognitive Impairment [PCI]) and objective tests of attention, processing speed, and executive function (APE domain) and learning and memory [LM domain]. Linear regression tested associations of pre-treatment tumor features and cognition, adjusting for age, race, and study site. HER2 positivity and higher stage (II/III vs. 0/I) were a priori predictors of cognition; in secondary analyses we explored associations of other tumor features and cognitive impairment (i.e., PCI score < 54 or having 2 tests < 1.5 SD or 1 test < 2 SD from the mean APE or LM domain score). RESULTS: HER2 positivity and the hormone receptor negative/HER2 + molecular subtype were associated with lower adjusted mean self-reported cognition scores and higher impairment rates (p values < .05). Higher stage of disease was associated with lower objective performance in APE. Other tumor features were associated with cognition in unadjusted and adjusted models, including larger tumor size and lower PCI scores (p = 0.02). Tumor features were not related to LM. CONCLUSIONS: Pre-adjuvant therapy cognition was associated with HER2 positivity and higher stage of disease and other features of aggressive tumors. Additional research is needed to confirm these results and assess potential mechanisms and clinical management strategies.

Randomized double-masked controlled trial of cognitive training in breast cancer survivors: a preliminary study.

PURPOSE: To evaluate the acceptability, satisfaction, and preliminary efficacy of cognitive training for improving cognitive function and health outcomes in breast cancer survivors (BCS). PATIENTS AND METHODS: BCS enrolled in this 2-group randomized, double-masked controlled trial of cognitive training. Primary outcomes included the acceptability and satisfaction of the interventions. Secondary outcomes included examining the effect size and reliable improvement of perceived cognitive function and health outcomes, including work ability, health perception (status and change), and quality of life. Exploratory outcomes were performance on neuropsychological tests and plasma levels of brain-derived neurotropic factor (BDNF). Data were collected at baseline and immediately post-intervention. Using ANCOVA models, the intervention was compared to attention control while adjusting for covariates and baseline values. The effect sizes for differences in means and the reliable improvement percentage were reported. RESULTS: Thirty-six BCS completed the study and were on average 57.6 (SD = 8.0) years old, 59.4% Caucasian, and had some college education (74.5%). Both programs were reported to be satisfactory and acceptable. Non-significant small effect sizes were noted for the intervention on cognitive abilities (d = 0.26) and cognitive concerns (d = - 0.32), with reliable improvement noted in 32% and 28% of BCS, respectively. Small to medium effect sizes were noted in improvement in work ability (d = 0.37) and health perception status (d = 0.30) and change (d = 0.60, p < 0.05). CONCLUSIONS: Cognitive training was acceptable to BCS and resulted in improvement in perceived cognitive function and perceptions of "real-world" health benefits. A larger randomized controlled trial is warranted to determine its effectiveness for objective cognitive performance.

Estradiol treatment in young postmenopausal women with self-reported cognitive complaints: Effects on cholinergic-mediated cognitive performance.

OBJECTIVE: Older women are at increased risk of developing Alzheimer's disease compared to men. One proposed reason is that following menopause there is a decline in estrogens. Estrogens are important for cholinergic functioning and attenuate the impact of cholinergic antagonists on cognitive performance in postmenopausal women. Self-reported or subjective cognitive complaints in middle or older age may represent a harbinger of cognitive decline and those who endorse cognitive complaints appear more likely to develop future cognitive impairment. However, the response of individuals with cognitive complaints after menopause to estrogen and the relationship to cholinergic functioning has not been investigated. This study investigated the effect of estrogen treatment using 17ß-estradiol on cognitive performance following anticholinergic blockade in postmenopausal women and the relationship of this interaction with the level of self-reported (subjective) postmenopausal cognitive complaints. METHODS: Forty postmenopausal women (aged 50-60 years) completed a 3-month treatment regimen of either 1 mg oral estradiol or placebo. Participants then completed four challenge days in which they completed cognitive and behavioral tasks after one of four cholinergic antagonist drug conditions (oral mecamylamine (MECA), intravenous scopolamine, combined MECA and scopolamine, or PLC). RESULTS: Compared to PLC, the estradiol treated group performed worse on attention tasks under cholinergic challenge including the choice reaction time task and the critical flicker fusion task. In addition, participants who endorsed greater cognitive complaints showed reduced performance on the N-back working memory task, regardless of whether they received estradiol treatment. CONCLUSIONS: The findings of this study indicate that estradiol treatment was unable to mitigate anticholinergic blockade in postmenopausal women with subjective cognitive complaints, and worsened performance on attention tasks. Moreover, the present study suggests that greater levels of cognitive complaints following menopause may be associated with an underlying decline in cholinergic function that may manifest as an inability to compensate during working memory tasks.

Loneliness and mental health during the COVID-19 pandemic in older breast cancer survivors and noncancer controls.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has had wide-ranging health effects and increased isolation. Older with cancer patients might be especially vulnerable to loneliness and poor mental health during the pandemic. METHODS: The authors included active participants enrolled in the longitudinal Thinking and Living With Cancer study of nonmetastatic breast cancer survivors aged 60 to 89 years (n = 262) and matched controls (n = 165) from 5 US regions. Participants completed questionnaires at parent study enrollment and then annually, including a web-based or telephone COVID-19 survey, between May 27 and September 11, 2020. Mixed-effects models were used to examine changes in loneliness (a single item on the Center for Epidemiologic Studies-Depression [CES-D] scale) from before to during the pandemic in survivors versus controls and to test survivor-control differences in the associations between changes in loneliness and changes in mental health, including depression (CES-D, excluding the loneliness item), anxiety (the State-Trait Anxiety Inventory), and perceived stress (the Perceived Stress Scale). Models were adjusted for age, race, county COVID-19 death rates, and time between assessments. RESULTS: Loneliness increased from before to during the pandemic (0.211; P = .001), with no survivor-control differences. Increased loneliness was associated with worsening depression (3.958; P < .001) and anxiety (3.242; P < .001) symptoms and higher stress (1.172; P < .001) during the pandemic, also with no survivor-control differences. CONCLUSIONS: Cancer survivors reported changes in loneliness and mental health similar to those reported by women without cancer. However, both groups reported increased loneliness from before to during the pandemic that was related to worsening mental health, suggesting that screening for loneliness during medical care interactions will be important for identifying all older women at risk for adverse mental health effects of the pandemic.

Symptom burden among older breast cancer survivors: The Thinking and Living With Cancer (TLC) study.

BACKGROUND: Little is known about longitudinal symptom burden, its consequences for well-being, and whether lifestyle moderates the burden in older survivors. METHODS: The authors report on 36-month data from survivors aged ≥60 years with newly diagnosed, nonmetastatic breast cancer and noncancer controls recruited from August 2010 through June 2016. Symptom burden was measured as the sum of self-reported symptoms/diseases as follows: pain (yes or no), fatigue (on the Functional Assessment of Cancer Therapy [FACT]-Fatigue scale), cognitive (on the FACT-Cognitive scale), sleep problems (yes or no), depression (on the Center for Epidemiologic Studies Depression scale), anxiety (on the State-Trait Anxiety Inventory), and cardiac problems and neuropathy (yes or no). Well-being was measured using the FACT-General scale, with scores from 0 to 100. Lifestyle included smoking, alcohol use, body mass index, physical activity, and leisure activities. Mixed models assessed relations between treatment group (chemotherapy with or without hormone therapy, hormone therapy only, and controls) and symptom burden, lifestyle, and covariates. Separate models tested the effects of fluctuations in symptom burden and lifestyle on function. RESULTS: All groups reported high baseline symptoms, and levels remained high over time; differences between survivors and controls were most notable for cognitive and sleep problems, anxiety, and neuropathy. The adjusted burden score was highest among chemotherapy-exposed survivors, followed by hormone therapy-exposed survivors versus controls (P < .001). The burden score was related to physical, emotional, and functional well-being (eg, survivors with lower vs higher burden scores had 12.4-point higher physical well-being scores). The composite lifestyle score was not related to symptom burden or well-being, but physical activity was significantly associated with each outcome (P < .005). CONCLUSIONS: Cancer and its treatments are associated with a higher level of actionable symptoms and greater loss of well-being over time in older breast cancer survivors than in comparable noncancer populations, suggesting the need for surveillance and opportunities for intervention.

Cognitive function prior to systemic therapy and subsequent well-being in older breast cancer survivors: Longitudinal findings from the Thinking and Living with Cancer Study.

OBJECTIVE: To investigate the relationships between self-reported and objectively measured cognitive function prior to systemic therapy and subsequent well-being outcomes over 24 months in older breast cancer survivors. METHODS: Data were from 397 women aged 60 to 98 diagnosed with non-metastatic breast cancer in the Thinking and Living with Cancer Study recruited from 2010-2016. Cognitive function was measured at baseline (following surgery, prior to systemic therapy) using neuropsychological assessments of attention, processing speed, and executive function (APE), learning and memory (LM), and the self-reported FACT-Cog scale. Well-being was measured using the FACT-G functional, physical, social, and emotional well-being domain scales at baseline and 12 and 24 months later, scaled from 0 (low) to 100 (high). Linear mixed-effects models assessed the relationships between each of baseline APE, LM, and FACT-Cog quartiles with well-being scores over 24 months, adjusted for confounding variables. RESULTS: At baseline, older survivors in the lowest APE, LM, and FACT-Cog score quartiles experienced poorer global well-being than those in the highest quartiles. At 24 months, older survivors tended to improve in well-being, and there were no differences according to baseline APE or LM scores. At 24 months, mean global well-being was 80.3 (95% CI: 76.2-84.3) among those in the lowest vs 86.6 (95% CI: 83.1-90.1) in the highest FACT-cog quartile, a clinically meaningful difference of 6.3 points (95% CI: 1.5-11.1). CONCLUSIONS: Among older breast cancer survivors, self-reported, but not objective cognitive impairments, were associated with lower global well-being over the first 2 years of survivorship.

Sleep disturbance and neurocognitive outcomes in older patients with breast cancer: Interaction with genotype.

BACKGROUND: Sleep disturbance and genetic profile are risks for cognitive decline in noncancer populations, yet their role in cancer-related cognitive problems remains understudied. This study examined whether sleep disturbance was associated with worse neurocognitive outcomes in breast cancer survivors and whether sleep effects on cognition varied by genotype. METHODS: Newly diagnosed female patients (n = 319) who were 60 years old or older and had stage 0 to III breast cancer were recruited from August 2010 to December 2015. Assessments were performed before systemic therapy and 12 and 24 months later. Neuropsychological testing measured attention, processing speed, executive function, learning, and memory; self-perceived cognitive functioning was also assessed. Sleep disturbance was defined by self-report of routine poor or restless sleep. Genotyping included APOE, BDNF, and COMT polymorphisms. Random effects fluctuation models tested associations of between-person and within-person differences in sleep, genotype, and sleep-genotype interactions and cognition and controlled for age, reading level, race, site, and treatment. RESULTS: One-third of the patients reported sleep disturbances at each time point. There was a sleep-APOE ε4 interaction (P = .001) in which patients with the APOE ε4 allele and sleep disturbances had significantly lower learning and memory scores than those who were APOE ε4-negative and without sleep disturbances. There was also a sleep disturbance-COMT genotype interaction (P = .02) in which COMT Val carriers with sleep disturbances had lower perceived cognition than noncarriers. CONCLUSIONS: Sleep disturbance was common and was associated with worse cognitive performance in older breast cancer survivors, especially those with a genetic risk for cognitive decline. Survivorship care should include sleep assessments and interventions to address sleep problems.

Protective variant for hippocampal atrophy identified by whole exome sequencing.

We used whole-exome sequencing to identify variants other than APOE associated with the rate of hippocampal atrophy in amnestic mild cognitive impairment. An in-silico predicted missense variant in REST (rs3796529) was found exclusively in subjects with slow hippocampal volume loss and validated using unbiased whole-brain analysis and meta-analysis across 5 independent cohorts. REST is a master regulator of neurogenesis and neuronal differentiation that has not been previously implicated in Alzheimer's disease. These findings nominate REST and its functional pathways as protective and illustrate the potential of combining next-generation sequencing with neuroimaging to discover novel disease mechanisms and potential therapeutic targets.

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.

GWAS of longitudinal amyloid accumulation on 18F-florbetapir PET in Alzheimer's disease implicates microglial activation gene IL1RAP.

Brain amyloid deposition is thought to be a seminal event in Alzheimer's disease. To identify genes influencing Alzheimer's disease pathogenesis, we performed a genome-wide association study of longitudinal change in brain amyloid burden measured by (18)F-florbetapir PET. A novel association with higher rates of amyloid accumulation independent from APOE (apolipoprotein E) ε4 status was identified in IL1RAP (interleukin-1 receptor accessory protein; rs12053868-G; P = 1.38 × 10(-9)) and was validated by deep sequencing. IL1RAP rs12053868-G carriers were more likely to progress from mild cognitive impairment to Alzheimer's disease and exhibited greater longitudinal temporal cortex atrophy on MRI. In independent cohorts rs12053868-G was associated with accelerated cognitive decline and lower cortical (11)C-PBR28 PET signal, a marker of microglial activation. These results suggest a crucial role of activated microglia in limiting amyloid accumulation and nominate the IL-1/IL1RAP pathway as a potential target for modulating this process.

Evaluating the impact of chemotherapy-induced peripheral neuropathy symptoms (CIPN-sx) on perceived ability to work in breast cancer survivors during the first year post-treatment.

PURPOSE: To describe the impact of chemotherapy-induced peripheral neuropathy symptoms (CIPN-sx) on breast cancer survivors' (BCS) perceived ability to work post-treatment. METHODS: The sample included 22 chemotherapy-treated (Ctx+) and 22 chemotherapy-naïve (Ctx-) female BCS. Data was collected at the following three time points: baseline (post-surgery, pre-chemotherapy), 1 month (1 M) post-chemotherapy, and approximately 1 year (1 Y) later. The presence, frequency, number, and severity of CIPN-sx were self-reported using the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity questionnaire (FACT/GOG-Ntx) version 4, a validated 11-item CIPN measure. Perceived ability to work was measured using an item from the Functional Well-Being subscale of the FACT/GOG-Ntx. RESULTS: At 1 Y, more than 50 % of Ctx+ reported discomfort, numbness, or tingling in their hands or feet; weakness; or difficulty feeling small objects. The presence, number, and severity of these symptoms were correlated with being less able to work for Ctx+ at 1 M but not 1 Y. Results of a regression analysis using CIPN-sx to predict work ability found that models combining (1) hand numbness and trouble feeling small objects, (2) trouble buttoning buttons and trouble feeling small objects, (3) foot numbness and foot pain, (4) foot numbness and trouble walking, and (5) trouble hearing and hand pain each predicted survivors who were "not at all" able to work at 1 M. CONCLUSIONS: Unresolved CIPN-sx may play a role in challenges working for BCS post-treatment. These findings highlight the need for research to explore the impact that CIPN-sx have on BCS' ability to work, as well as the development of interventions to improve work function in BCS with CIPN-sx.

Longitudinal assessment of cognitive changes associated with adjuvant treatment for breast cancer: the impact of APOE and smoking.

PURPOSE: This study examined the association of post-treatment changes in cognitive performance, apolipoprotein E (APOE), and smoking in breast cancer patients treated with adjuvant therapy. PARTICIPANTS AND METHODS: Breast cancer patients treated with chemotherapy (N = 55, age = 51.9 ± 7.1, education = 15.7 ± 2.6) were evaluated with a battery of neuropsychological tests prior to chemotherapy and at 1, 6, and 18 months post-chemotherapy. Matched groups of breast cancer patients not exposed to chemotherapy (N = 68, age = 56.8 ± 8.3, education = 14.8 ± 2.2) and healthy controls (N = 43, age = 53.0 ± 10.1, education = 15.2 ± 2.6) were evaluated at similar intervals. APOE epsilon 4 carrier status (APOE4+) and smoking history were also evaluated. RESULTS: The detrimental effect of APOE4+ genotype on post-treatment cognitive functioning was moderated by smoking history, that is, patients without a smoking history had significantly lower performance on measures of processing speed and working memory compared with those with a smoking history and healthy controls. Exploratory analyses revealed that APOE4+ patients without a smoking history who were exposed to chemotherapy showed a decline in performance in processing speed, compared with patients with a smoking history. A similar but less pronounced pattern was seen in the no chemotherapy group (primarily endocrine treatment). For working memory, the APOE4+ by smoking interaction was observed in the no chemotherapy group only. CONCLUSIONS: The association between APOE status, breast cancer treatment, and cognitive functioning was moderated by smoking history suggesting that both chemotherapy and endocrine therapy interact with APOE status and smoking to influence cognition. A putative mechanism is that smoking corrects a deficit in nicotinic receptor functioning and dopamine levels in APOE4+ individuals.

Edge time series components of functional connectivity and cognitive function in Alzheimer's disease.

Understanding the interrelationships of brain function as measured by resting-state magnetic resonance imaging and neuropsychological/behavioral measures in Alzheimer's disease is key for advancement of neuroimaging analysis methods in clinical research. The edge time-series framework recently developed in the field of network neuroscience, in combination with other network science methods, allows for investigations of brain-behavior relationships that are not possible with conventional functional connectivity methods. Data from the Indiana Alzheimer's Disease Research Center sample (53 cognitively normal control, 47 subjective cognitive decline, 32 mild cognitive impairment, and 20 Alzheimer's disease participants) were used to investigate relationships between functional connectivity components, each derived from a subset of time points based on co-fluctuation of regional signals, and measures of domain-specific neuropsychological functions. Multiple relationships were identified with the component approach that were not found with conventional functional connectivity. These involved attentional, limbic, frontoparietal, and default mode systems and their interactions, which were shown to couple with cognitive, executive, language, and attention neuropsychological domains. Additionally, overlapping results were obtained with two different statistical strategies (network contingency correlation analysis and network-based statistics correlation). Results demonstrate that connectivity components derived from edge time-series based on co-fluctuation reveal disease-relevant relationships not observed with conventional static functional connectivity.

Prediction of cognitive decline in older breast cancer survivors: the Thinking and Living with Cancer study.

PURPOSE: Cancer survivors commonly report cognitive declines after cancer therapy. Due to the complex etiology of cancer-related cognitive decline (CRCD), predicting who will be at risk of CRCD remains a clinical challenge. We developed a model to predict breast cancer survivors who would experience CRCD after systematic treatment. METHODS: We used the Thinking and Living with Cancer study, a large ongoing multisite prospective study of older breast cancer survivors with complete assessments pre-systemic therapy, 12 months and 24 months after initiation of systemic therapy. Cognition was measured using neuropsychological testing of attention, processing speed, and executive function (APE). CRCD was defined as a 0.25 SD (of observed changes from baseline to 12 months in matched controls) decline or greater in APE score from baseline to 12 months (transient) or persistent as a decline 0.25 SD or greater sustained to 24 months. We used machine learning approaches to predict CRCD using baseline demographics, tumor characteristics and treatment, genotypes, comorbidity, and self-reported physical, psychosocial, and cognitive function. RESULTS: Thirty-two percent of survivors had transient cognitive decline, and 41% of these women experienced persistent decline. Prediction of CRCD was good: yielding an area under the curve of 0.75 and 0.79 for transient and persistent decline, respectively. Variables most informative in predicting CRCD included apolipoprotein E4 positivity, tumor HER2 positivity, obesity, cardiovascular comorbidities, more prescription medications, and higher baseline APE score. CONCLUSIONS: Our proof-of-concept tool demonstrates our prediction models are potentially useful to predict risk of CRCD. Future research is needed to validate this approach for predicting CRCD in routine practice settings.

Alzheimer's disease-related biomarkers and cancer-related cognitive decline: the thinking and living with cancer study.

PURPOSE: We evaluated whether plasma Alzheimer's Disease (AD)-related biomarkers were associated with cancer-related cognitive decline (CRCD) among older breast cancer survivors. METHODS: We included survivors 60-90 years with primary stage 0-III breast cancers (n = 236) and frequency-matched non-cancer controls (n = 154) who passed a cognitive screen and had banked plasma specimens. Participants were assessed at baseline (pre-systemic therapy) and annually for up to 60-months. Cognition was measured using tests of attention, processing speed and executive function (APE) and learning and memory (LM); perceived cognition was measured by the FACT-Cog PCI. Baseline plasma neurofilament light (NfL), glial fibrillary acidic protein (GFAP), beta-amyloid 42/40 (Aß42/40) and phosphorylated tau (p-tau181) were assayed using single molecule arrays. Mixed models tested associations between cognition and baseline AD-biomarkers, time, group (survivor vs control) and their two- and three-way interactions, controlling for age, race, WRAT4 Word Reading score, comorbidity and BMI; two-sided 0.05 p-values were considered statistically significant. RESULTS: There were no group differences in baseline AD-related biomarkers except survivors had higher baseline NfL levels than controls (p = .013). Survivors had lower adjusted longitudinal APE than controls starting from baseline and continuing over time (p = <0.002). However, baseline AD-related biomarker levels were not independently associated with adjusted cognition over time, except controls had lower APE scores with higher GFAP levels (p = .008). CONCLUSION: The results do not support a relationship between baseline AD-related biomarkers and CRCD. Further investigation is warranted to confirm the findings, test effects of longitudinal changes in AD-related biomarkers and examine other mechanisms and factors affecting cognition pre-systemic therapy.