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.

Social relationships and epigenetic aging in older adulthood: Results from the Health and Retirement Study.

Growing evidence suggests that social relationship quality can influence age-related health outcomes, although how the quality of one's relationships directly relates to the underlying aging process is less clear. We hypothesized that the absence of close relationships as well as lower support and higher strain within existing relationships would be associated with an accelerated epigenetic aging profile among older adults in the Health and Retirement Study. Adults (N = 3,647) aged 50-100 years completed ratings of support and strain in relationships with their spouse, children, other family members, and friends. They also provided a blood sample that was used for DNA methylation profiling to calculate a priori-specified epigenetic aging measures: Horvath, Hannum, PhenoAge, GrimAge, and Dunedin Pace of Aging methylation (DunedinPoAm38). Generalized linear models that adjusted for chronological age, sex, and race/ethnicity and applied a false discovery rate correction revealed that the absence of marital and friend relationships related to an older GrimAge and faster DunedinPoAm38. Among those with existing relationships, lower support from a spouse, child, other family, and friends and higher strain with friends related to an older PhenoAge and GrimAge and faster DunedinPoAm38. In secondary analyses that further adjusted for socioeconomic and lifestyle factors, lower support from other family members and friends was associated with greater epigenetic aging. Findings suggest that the absence of close relationships and lower support within existing relationships-particularly with family members and friends-relate to accelerated epigenetic aging in older adulthood, offering one mechanism through which social relationships might influence risk for age-related declines and disease.

Diversity, equity, and inclusivity in observational ambulatory assessment: Recommendations from two decades of Electronically Activated Recorder (EAR) research.

Ambient audio sampling methods such as the Electronically Activated Recorder (EAR) have become increasingly prominent in clinical and social sciences research. These methods record snippets of naturalistically assessed audio from participants' daily lives, enabling novel observational research about the daily social interactions, identities, environments, behaviors, and speech of populations of interest. In practice, these scientific opportunities are equaled by methodological challenges: researchers' own cultural backgrounds and identities can easily and unknowingly permeate the collection, coding, analysis, and interpretation of social data from daily life. Ambient audio sampling poses unique and significant challenges to cultural humility, diversity, equity, and inclusivity (DEI) in scientific research that require systematized attention. Motivated by this observation, an international consortium of 21 researchers who have used ambient audio sampling methodologies created a workgroup with the aim of improving upon existing published guidelines. We pooled formally and informally documented challenges pertaining to DEI in ambient audio sampling from our collective experience on 40+ studies (most of which used the EAR app) in clinical and healthy populations ranging from children to older adults. This article presents our resultant recommendations and argues for the incorporation of community-engaged research methods in observational ambulatory assessment designs looking forward. We provide concrete recommendations across each stage typical of an ambient audio sampling study (recruiting and enrolling participants, developing coding systems, training coders, handling multi-linguistic participants, data analysis and interpretation, and dissemination of results) as well as guiding questions that can be used to adapt these recommendations to project-specific constraints and needs.

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.

Stress-induced biological aging: A review and guide for research priorities.

Exposure to chronic adverse conditions, and the resultant activation of the neurobiological response cascade, has been associated with an increased risk of early onset of age-related disease and, recently, with an older biological age. This body of research has led to the hypothesis that exposure to stressful life experiences, when occurring repeatedly or over a prolonged period, may accelerate the rate at which the body ages. The mechanisms through which chronic psychosocial stress influences distinct biological aging pathways to alter rates of aging likely involve multiple layers in the physiological-molecular network. In this review, we integrate research using animal, human, and in vitro models to begin to delineate the distinct pathways through which chronic psychosocial stress may impact biological aging, as well as the neuroendocrine mediators (i.e., norepinephrine, epinephrine, and glucocorticoids) that may drive these effects. Findings highlight key connections between stress and aging, namely cellular metabolic activity, DNA damage, telomere length, cellular senescence, and inflammatory response patterns. We conclude with a guiding framework and conceptual model that outlines the most promising biological pathways by which chronic adverse conditions could accelerate aging and point to key missing gaps in knowledge where future research could best answer these pressing questions.

Early-life stress, depressive symptoms, and inflammation: the role of social factors.

OBJECTIVE: To identify modifiable, social factors that moderate the relationship between early-life stress (ELS) and health outcomes as measured by depressive symptoms and inflammation. METHODS: Data were from 3,416 adults (58.28% female), ages 36 - 97 (Mage = 68.41; SDage = 10.24) who participated in the 2006 wave of the Health and Retirement Study, a nationally representative sample of older adults in the United States. This study used hierarchical regression analyses to first test the main effects of ELS on depressive symptoms and inflammation (high-sensitivity C-reactive protein). Four social factors (perceived support, frequency of social contact, network size, and volunteer activity) were assessed as moderators of the ELS-depression and ELS-inflammation relationships. RESULTS: There was a small, positive association between ELS and depressive symptoms (B = 0.17, SE = 0.05, p = .002), which was moderated by social contact and perceived support. Specifically, ELS was only associated with elevated depressive symptoms for participants with limited social contact (B = 0.24, SE = 0.07, p < .001) and low perceived support (B = 0.24, SE = 0.07, p < .001). These associations remained after accounting for potential confounds (age, body-mass index, adulthood stress, and marital status). CONCLUSIONS: Increased social contact and perceived support may be protective for individuals at a higher risk of developing depressive symptoms as a result of ELS. Future interventions may benefit from leveraging these social factors to improve quality of life in adults with ELS.

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.

Psychosocial Stressors and Telomere Length: A Current Review of the Science.

A growing literature suggests that exposure to adverse social conditions may accelerate biological aging, offering one mechanism through which adversity may increase risk for age-related disease. As one of the most extensively studied biological markers of aging, telomere length (TL) provides a valuable tool to understand potential influences of social adversity on the aging process. Indeed, a sizeable literature now links a wide range of stressors to TL across the life span. The aim of this article is to review and evaluate this extant literature with a focus on studies that investigate psychosocial stress exposures and experiences in early life and adulthood. We conclude by outlining potential biological and behavioral mechanisms through which psychosocial stress may influence TL, and we discuss directions for future research in this area.

Sleep disturbances and inflammatory gene expression among pregnant women: Differential responses by race.

Excessive inflammation in pregnancy predicts adverse birth outcomes, including shortened gestational length and lower birthweight, with African American women at greater risk. As substantial racial disparities in sleep quality, and evidence that African Americans have increased vulnerability for sleep-induced inflammatory dysregulation, sleep may be a critical, modifiable health behavior that contributes to racial disparities in birth outcomes. The present study examined sleep disturbance as a predictor of genome-wide transcriptome profiles of peripheral blood samples from 103 pregnant women (33 African American, 70 white) assessed at 18.7 ± 7.2 weeks gestation. We hypothesized that pregnant women with significant sleep disturbances would have gene expression profiles indicating over-expression of inflammatory pathways, with greater effects among African American compared to white women. Promoter-based bioinformatics analyses of differentially expressed genes indicated greater activation of NF-кB, AP1, and CREB transcription factors among African American women with sleep disturbances (all p < 0.05), and enhanced activation of AP1, but not NF-кB and reduced CREB activity among white women with sleep disturbances (p < 0.05). Differences in glucocorticoid receptor (GR) activity were also observed, in which African American women with sleep disturbances had reduced GR activity (p < 0.05), but white women with sleep disturbances showed a trend for enhanced GR activity (p = 0.11). Similarly, Interferon Response Factor (IRF) activity was reduced in African American women while increased in white women with sleep disturbances (p < 0.05). The current study provides novel evidence for gene expression related to inflammation, glucocorticoids, and anti-viral immunity among pregnant women with sleep disturbances, with differential effects by race. African Americans showed greater breadth and magnitude in these proinflammatory and anti-viral pathways than whites, with divergence in anti-inflammatory glucocorticoid, proinflammatory adrenergic-mediated cAMP, and anti-viral interferon responses. These data elucidate the role of sleep disturbances in intracellular inflammatory and anti-viral immunity in pregnancy and provide a potential target for intervention.

Best practices for Electronically Activated Recorder (EAR) research: A practical guide to coding and processing EAR data.

Since its introduction in 2001, the Electronically Activated Recorder (EAR) method has become an established and broadly used tool for the naturalistic observation of daily social behavior in clinical, health, personality, and social science research. Previous treatments of the method have focused primarily on its measurement approach (relative to other ecological assessment methods), research design considerations (e.g., sampling schemes, privacy considerations), and the properties of its data (i.e., reliability, validity, and added measurement value). However, the evolved procedures and practices related to arguably one of the most critical parts of EAR research-the coding process that converts the sampled raw ambient sounds into quantitative behavioral data for statistical analysis-so far have largely been communicated informally between EAR researchers. This article documents "best practices" for processing EAR data, which have been tested and refined in our research over the years. Our aim is to provide practical information on important topics such as the development of a coding system, the training and supervision of EAR coders, EAR data preparation and database optimization, the troubleshooting of common coding challenges, and coding considerations specific to diverse populations.

Preliminary evidence that androgen signaling is correlated with men's everyday language.

OBJECTIVES: Testosterone (T) has an integral, albeit complex, relationship with social behavior, especially in the domains of aggression and competition. However, examining this relationship in humans is challenging given the often covert and subtle nature of human aggression and status-seeking. The present study aimed to investigate whether T levels and genetic polymorphisms in the AR gene are associated with social behavior assessed via natural language use. METHODS: We used unobtrusive, behavioral, real-world ambulatory assessments of men in partnered heterosexual relationships to examine the relationship between plasma T levels, variation in the androgen receptor (AR) gene, and spontaneous, everyday language in three interpersonal contexts: with romantic partners, with co-workers, and with their children. RESULTS: Men's T levels were positively correlated with their use of achievement words with their children, and the number of AR CAG trinucleotide repeats was inversely correlated with their use of anger and reward words with their children. T levels were positively correlated with sexual language and with use of swear words in the presence of their partner, but not in the presence of co-workers or children. CONCLUSIONS: Together, these results suggest that T may influence social behavior by increasing the frequency of words related to aggression, sexuality, and status, and that it may alter the quality of interactions with an intimate partner by amplifying emotions via swearing.

Partner Pronoun Use, Communal Coping, and Abstinence during Couple-Focused Intervention for Problematic Alcohol Use.

Communal coping-a process in which romantic partners view a problem as ours rather than yours or mine, and take collaborative action to address it -has emerged as an important predictor of health and treatment outcomes. In a study of partners' pronoun use prior to and during couple-focused alcohol interventions, we examined first-person plural (we-talk) and singular (I-talk) pronouns as linguistic markers of communal coping and behavioral predictors of treatment outcome. Thirty-three couples in which one partner abused alcohol were selected from a randomized control trial (N = 63) of couple-focused Cognitive-Behavioral or Family Systems Therapy if they had unambiguously successful or unsuccessful treatment outcomes (i.e., patient maintained abstinence for 30 days prior to treatment termination or had more than one heavy drinking day in the same period). Pronoun measures for each partner were obtained via computerized text analysis from transcripts of partners' speech, derived from a videotaped pretreatment interaction task and three subsequent therapy sessions. Spouse we-talk during the intervention (accounting for pretreatment we-talk), as an index of communal orientation, uniquely predicted successful treatment outcomes. In contrast, both patient and spouse I-talk during the intervention (accounting for pretreatment I-talk), as a marker of individualistic orientation, uniquely predicted unsuccessful outcomes, especially when distinguishing active and passive (I vs. me/my) pronoun forms. Results strengthen evidence for the prognostic significance of spouse behavior for patient health outcomes and for communal coping (indexed via pronoun use) as a potential mechanism of change in couple-focused interventions for health problems.

A Semantic Corpus Comparison Analysis of Couple-Focused Interventions for Problematic Alcohol Use.

Incorporating spouses into interventions for problematic alcohol use is associated with increased efficacy; yet, little is known about the therapeutic processes that may explain these effects. In a study of partner language use during couple-focused alcohol interventions, we utilized a linguistic corpus comparison tool, Wmatrix, to identify semantic themes that differentiated couples with successful and unsuccessful treatment outcomes and may therefore also reflect potential change processes. Thirty-three couples participated in a randomized control trial of Family Systems Therapy (FST) or Cognitive Behavioural Therapy (CBT). Linguistic comparisons of partners' speech during the therapy sessions suggested that drinks and alcohol was a significant differentiating semantic theme. Specifically, patients and spouses in FST with successful outcomes used more language related to drinks and alcohol than patients and spouses in FST with unsuccessful outcomes. Post-hoc analyses of context suggested that, in FST, successful spouses spoke less about the patient's drinking and more about alcohol in general (without reference to an individual) than unsuccessful spouses. Conversely, spouses in CBT with successful outcomes used less language related to drinks and alcohol than spouses in CBT with unsuccessful outcomes. In CBT, successful spouses spoke more about the patient's and couple's drinking and less about the spouse's and other people's drinking than unsuccessful spouses. Results emphasize the role of spouse behaviour-in this case indexed via language use-in alcohol treatment outcomes. Findings also suggest potentially distinct therapeutic processes in FST and CBT and highlight the utility of linguistic corpus comparison methods in couple-focused intervention research. Copyright © 2016 John Wiley & Sons, Ltd. KEY PRACTITIONER MESSAGE: Incorporating spouses into interventions for problematic alcohol use is associated with increased efficacy; yet, little is known about the specific therapeutic processes that may explain these effects. Findings from this study suggest that semantic themes such as drinks and alcohol in partner speech during therapy sessions differentiate successful and unsuccessful treatment outcomes among couples participating in two couple-focused interventions for problematic alcohol use. In addition, the context in which partners used alcohol-related language differed by intervention type and treatment outcome, which suggests potential therapeutic processes that are unique to the two interventions (Family Systems versus Cognitive Behavioural Therapy).

Associations of religious and existential variables with psychosocial factors and biomarkers of cardiovascular risk in bereavement.

Bereavement increases in prevalence as people age and is associated with multiple psychological and health risks, including cardiovascular risk. Religious and existential variables may play an important role in the health impacts of bereavement. Theorized pathways linking religious and existential variables with health have suggested these associations are due to intermediary psychosocial variables, but have not been tested in bereavement. This research empirically tested these pathways in a bereaved population. In N = 73 adults within 1 year of bereavement (mean age = 64.36), this study examined associations between (1) religious and existential characteristics (religious and spiritual struggles, intrinsic religiosity, and existential quest) and intermediary psychosocial variables (depression, loneliness, and difficulties in emotion regulation), and between (2) intermediary psychosocial variables and bereavement-relevant health outcomes (self-reported health, change in health since last year, grief severity, and cardiovascular biomarkers). Cardiovascular biomarkers (heart rate, heart rate variability, and blood pressure) were collected before, during, and after a laboratory grief recall emotion elicitation. Anticipated associations between self-reported religious and existential characteristics and intermediary variables, and between intermediary variables and self-reported bereavement-relevant outcomes, were consistently observed. However, associations between intermediary variables and cardiovascular biomarkers were largely unobserved. This study examined the role of religious and existential variables in whole-person health after bereavement and is among the first to include biomarkers of cardiovascular risk. Results suggest that although religious and existential variables are associated with important bereavement-related outcomes, these associations may be "skin-deep," and extensions to cardiovascular functioning should be re-examined.

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.

Elevated C-Reactive Protein and Subsequent Patient-Reported Cognitive Problems in Older Breast Cancer Survivors: The Thinking and Living With Cancer Study.

PURPOSE: To examine longitudinal relationships between levels of C-reactive protein (CRP) and cognition in older breast cancer survivors and noncancer controls. METHODS: English-speaking women age ≥ 60 years, newly diagnosed with primary breast cancer (stage 0-III), and frequency-matched controls were enrolled from September 2010 to March 2020; women with dementia, neurologic disorders, and other cancers were excluded. Assessments occurred presystemic therapy/enrollment and at annual visits up to 60 months. Cognition was measured using the Functional Assessment of Cancer Therapy-Cognitive Function and neuropsychological testing. Mixed linear effect models tested for survivor-control differences in natural log (ln)-transformed CRP at each visit. Random effect-lagged fluctuation models tested directional effects of ln-CRP on subsequent cognition. All models controlled for age, race, study site, cognitive reserve, obesity, and comorbidities; secondary analyses evaluated if depression or anxiety affected results. RESULTS: There were 400 survivors and 329 controls with CRP specimens and follow-up data (average age of 67.7 years; range, 60-90 years). The majority of survivors had stage I (60.9%), estrogen receptor-positive (87.6%) tumors. Survivors had significantly higher adjusted mean ln-CRP than controls at baseline and 12-, 24-, and 60-month visits (all P < .05). Higher adjusted ln-CRP predicted lower participant-reported cognition on subsequent visits among survivors, but not controls (P interaction = .008); effects were unchanged by depression or anxiety. Overall, survivors had adjusted Functional Assessment of Cancer Therapy-Cognitive Function scores that were 9.5 and 14.2 points lower than controls at CRP levels of 3.0 and 10.0 mg/L. Survivors had poorer neuropsychological test performance (v controls), with significant interactions with CRP only for the Trails B test. CONCLUSION: Longitudinal relationships between CRP and cognition in older breast cancer survivors suggest that chronic inflammation may play a role in development of cognitive problems. CRP testing could be clinically useful in survivorship care.

Depressive symptom trajectories in older breast cancer survivors: the Thinking and Living with Cancer Study.

PURPOSE: To identify trajectories of depressive symptoms in older breast cancer survivors and demographic, psychosocial, physical health, and cancer-related predictors of these trajectories. METHODS: Recently diagnosed nonmetastatic breast cancer survivors (n = 272), ages 60-98 years, were evaluated for depressive symptoms (Center for Epidemiological Studies Depression Scale, CES-D; scores ≥16 suggestive of clinically significant depressive symptoms). CES-D scores were analyzed in growth-mixture models to determine depression trajectories from baseline (post-surgery, pre-systemic therapy) through 3-year annual follow-up. Multivariable, multinomial logistic regression was used to identify baseline predictors of depression trajectories. RESULTS: Survivors had three distinct trajectories: stable (84.6%), emerging depressive symptoms (10.3%), and recovery from high depressive symptoms at baseline that improved slowly over time (5.1%). Compared to stable survivors, those in the emerging (OR = 1.16; 95% CI = 1.08-1.23) or recovery (OR = 1.26; 95% CI = 1.15-1.38) groups reported greater baseline anxiety. Greater baseline deficit accumulation (frailty composite measure) was associated with emerging depressive symptoms (OR = 3.71; 95% CI = 1.90-7.26). Less social support at baseline (OR = 0.38; 95% CI = 0.15-0.99), but greater improvement in emotional (F = 4.13; p = 0.0006) and tangible (F = 2.86; p = 0.01) social support over time, was associated with recovery from depressive symptoms. CONCLUSIONS: Fifteen percent of older breast cancer survivors experienced emerging or recovery depressive symptom trajectories. Baseline anxiety, deficit accumulation, and lower social support were associated with worse outcomes. IMPLICATIONS FOR CANCER SURVIVORS: Our results emphasize the importance of depression screening throughout the course of cancer care to facilitate early intervention. Factors associated with depressive symptoms, including lower levels of social support proximal to diagnosis, could serve as intervention levers.

Chronic stress increases transcriptomic indicators of biological aging in mouse bone marrow leukocytes.

Research with animals and humans has demonstrated that chronic stress exposure can impact key biological aging pathways such as inflammation and DNA damage, suggesting a mechanism through which stress may increase risk for age-related disease. However, it is less clear whether these effects extend to other hallmarks of the aging process, such as cellular senescence. Male SCID mice were exposed to 14 days of restraint stress, with (n â€‹= â€‹6) or without (n â€‹= â€‹10) propranolol administration, or a non-stress control condition (n â€‹= â€‹10). Normal femoral bone marrow leukocytes were isolated from engrafted leukemia cells that had been injected prior to the stressor, as the mice were also under a cancer challenge. We performed whole genome transcriptional profiling to assess indicators of biological aging: cell stress, DNA damage repair, cellular senescence markers p16INK4a and p21, and the pro-inflammatory senescence-associated secretory phenotype (SASP). ANCOVAs that adjusted for tumor load and Fisher's pairwise comparisons revealed that stressed mice had enhanced p16INK4a (p â€‹= â€‹.02) and p21 (p â€‹= â€‹.004), lower DNA damage repair (p â€‹< â€‹.001), and higher SASP (p â€‹= â€‹.03) gene expression than control mice. Stressed mice also showed up-regulated beta-adrenergic (CREB) and inflammatory (NF-кB, AP-1) and down-regulated cell stress (Nrf2) transcription factor activity relative to control mice (ps â€‹< â€‹.01). Propranolol reversed CREB and Nrf2 activity (ps â€‹< â€‹.03). Findings suggest that chronic stress exposure can impact several key biological aging pathways within bone marrow leukocytes and these effects may be partially mediated by sympathetic beta-adrenergic receptor activation.